Carboxamide derivatives useful as rsk inhibitors

ABSTRACT

Described herein are carboxamide derivatives that are useful as inhibitors of p90 ribosomal S6 kinase (RSK), pharmaceutical compositions comprising the derivatives, and methods of using the derivatives in treating diseases or conditions associated with RSK activity. Such carboxamide derivatives form bicyclic and tricyclic ring systems and the disease or condition associated with RSK activity in a mammal is cancer.

CROSS-REFERENCE

This application claims benefit of U.S. Provisional Application No.62/297,522, filed on Feb. 19, 2016, which is herein incorporated byreference in its entirety.

FIELD OF THE INVENTION

Described herein are carboxamide derivatives and pharmaceuticalcompositions comprising the compounds and methods of using the compoundsand the pharmaceutical compositions in treating diseases or conditions,such as cancer, as well as other diseases and conditions associated withthe p90 ribosomal S6 kinase (RSK).

BACKGROUND OF THE INVENTION

The p90 ribosomal S6 kinase (RSK) family is comprised of four isoforms,RSK1, RSK2, RSK3 and RSK4. These isoforms are pivotal for transmittingcell signalling from cell surface receptors such as growth factors,hormones, and cytokines. RSK1 and RSK2 are the isoforms most common tocancer where they control cell growth, invasion and the suppression ofapoptosis. RSK3 is not commonly expressed in cancer, however, it hasbeen associated with drug resistance as have RSK1 and RSK2. RSK4 is notcommonly expressed in cancer. The RSK family is also fundamental toinflammation, diabetes and heart disease.

In the field of oncology, RSK inhibitors provide an opportunity fortargeted therapy to improve the treatment of cancer. Inhibiting RSK alsoaffords an opportunity to overcome drug resistance through multiplemechanisms including the elimination of cancer stem cells (CSC) ortumor-initiating cells (TIC). RSK inhibitors can reportedly overcomeresistance to targeted therapies such as Herceptin, Gefitinib, andEnzalutamide. RSK inhibitors can also be used to augment resistance tomicrotubule cytotoxics such as paclitaxel.

There are many types of cancers associated with RSK activity, including,but not limited to, breast, prostate, lung, brain, blood, skin, bone,and ovarian cancers. In the field of breast and prostate cancerresearch, RSK inhibitors have been shown to block hormone signalling. Aswith many types of cancer, those that arise in the breast aregenetically diverse and as such have been categorized into three maintypes: Type 1, which is hormone positive expressing the estrogen andprogresterone receptors (ER and PR respectively); Type 2, which is Her-2positive; and Type 3, which is triple-negative as the cancer cells lackER, PR and Her-2 receptors. The triple-negative breast cancer (TNBC) iscurrently considered the most aggressive and is associated with theworst outcomes for patients. It constitutes 15-25% of all breast cancersand is more common in younger women. Women with mutations in the breastcancer susceptibility genes 1 and 2 (BRCA1 and BRCA2) are more likely todevelop TNBC then the other types of breast cancer.

Accordingly, there is a need for small molecule inhibitors of RSK whichare useful in treating diseases and conditions associated with theactivity of RSK, such as cancer.

SUMMARY OF THE INVENTION

In one aspect described herein, are compounds which are useful ininhibiting RSK activity. In some embodiments described herein, arecompounds of formula (I):

wherein:

-   n is 1 or 2;-   A is —N═ or —C(R³)═;-   B is —O—, —N(R⁴)—, or —S(O)_(t) (where t is 0, 1 or 2)-;-   E is —N═ or —C(R³)═;-   R¹ is R⁵—C(O)N(R⁶)—, R⁷—N(R⁶)C(O)—, R⁵—N(R⁶)C(O)N(R⁶)—, or    R⁵—N(R⁶)C(═NR⁶)N(R⁶)—;-   each R² is independently hydrogen, alkyl, halo, haloalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;-   or two R², together with the adjacent carbons to which they are    attached, form a fused optionally substituted 6-membered    N-heterocyclyl;-   each R³ is independently hydrogen, alkyl, haloalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl or optionally    substituted heteroarylalkyl;-   R⁴ is hydrogen, alkyl, haloalkyl, optionally substituted aryl or    optionally substituted aralkyl;-   or R⁴, together with the nitrogen to which it is attached, and a R²,    together with the adjacent carbon to which it is attached, together    form a fused 6-membered N-heterocyclyl of the following structure:

-   where    indicates the point of fusion and R^(4a), R^(4b), R^(4c), and R^(4d)    are each independently hydrogen, alkyl, halo or haloalkyl or R^(4a)    and R^(4b), together with the carbon to which they are both    attached, form a cycloalkyl or R^(4c) and R^(4d), together with the    carbon to which they are both attached, form a cycloalkyl, and the    remaining R², if present, is selected from hydrogen, alkyl, halo or    haloalkyl;-   R⁵ is optionally substituted aryl or optionally substituted    N-heteroaryl;-   each R⁶ is independently hydrogen, alkyl, haloalkyl, optionally    substituted aryl or optionally substituted aralkyl;-   R⁷ is optionally substituted aryl or optionally substituted    N-heteroaryl when E is —N═;-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and one R² is halo, haloalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and one of R^(4a) and R^(4b)    is not methyl and the other is not hydrogen;-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and two of R^(4a), R^(4b),    R^(4c), and R^(4d) on adjacent carbons are not both methyl and the    other two are not both hydrogen;-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and R^(4a) and R^(4b),    together with the carbon to which they are both attached, form a    cycloalkyl or R^(4c) and R^(4d), together with the carbon to which    they are both attached, form a cycloalkyl;-   or R⁷ is a monocyclic N-heteroaryl substituted by an aralkyl    substituted with halo, haloalkyl, —CN, —NO₂, —N(R⁶)₂, —N(R⁶)C(O)OR⁶,    —C(O)R⁶, —C(O)OR⁶ or —C(O)N(R⁶)₂ when E is —C(R³)═ and R^(4a) is    methyl and R^(4b), R^(4c), and R^(4d) are each hydrogen or when E is    —C(R³)═ and R^(4a) and R^(4c) are each methyl and R^(4b) and R^(4d)    are each hydrogen;-   or R⁷ is a monocyclic N-heteroaryl substituted with optionally    substituted N-heterocyclylalkyl when E is —C(R³)═;-   as an individual stereoisomer, enantiomer or tautomer thereof or a    mixture thereof;-   or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another aspect is a compound of formula (II) having the structure:

wherein:

-   R² is independently hydrogen, halo, C₁₋₆alkyl, or C₁₋₆haloalkyl;-   R^(4a) and R^(4b) are each independently hydrogen, halo, C₁₋₆alkyl,    or C₁₋₆haloalkyl; or R^(4a) and R^(4b), together with the carbon to    which they are both attached, form a cycloalkyl;-   each R⁶ is independently hydrogen or C₁₋₆alkyl;-   R¹¹ is halo, C₁₋₆haloalkyl, —N(R⁶)₂, —C₁₋₆alkyl-N(R⁶)₂, or    —C(O)N(R⁶)₂;-   each R¹² is independently —OH, —CN, halo, C₁₋₆alkyl, C₁₋₆haloalkyl,    C₁₋₆alkoxy, C₁₋₆haloalkoxy, —N(R⁶)₂, —C₁₋₆alkyl-N(R⁶)₂, —C(O)R⁶,    —C(O)OR⁶, —C(O)N(R⁶)₂, aryl, aralkyl, cycloalkyl, heterocyclyl, or    heteroaryl; and-   n is 0, 1, 2, 3, or 4;-   as an individual stereoisomer, enantiomer or tautomer thereof or a    mixture thereof;-   or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In some embodiments is a compound of formula (II) wherein R² ishydrogen. In some embodiments is a compound of formula (II) wherein R²is halo. In some embodiments is a compound of formula (II) wherein R² is—F. In some embodiments is a compound of formula (II) wherein R² is —Cl.In some embodiments is a compound of formula (II) wherein R² is C₁₋₆alkyl. In some embodiments is a compound of formula (II) wherein R² is—CH₃. In some embodiments is a compound of formula (II) wherein R^(4a)is C₁₋₆alkyl. In some embodiments is a compound of formula (II) whereinR^(4a) is —CH₃. In some embodiments is a compound of formula (II)wherein R^(4b) is hydrogen. In some embodiments is a compound of formula(II) wherein each R¹² is independently —OH, —CN, halo, C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, —N(R⁶)₂, —C₁₋₆alkyl-N(R⁶)₂,—C(O)R⁶, —C(O)OR⁶, or —C(O)N(R⁶)₂. In some embodiments is a compound offormula (II) wherein each R¹² is independently halo, C₁₋₆alkyl, —N(R⁶)₂,—C₁₋₆alkyl-N(R⁶)₂, or C₁₋₆haloalkyl. In some embodiments is a compoundof formula (II) wherein n is 1. In some embodiments is a compound offormula (II) wherein n is 0. In some embodiments is a compound offormula (II) wherein R¹¹ is halo. In some embodiments is a compound offormula (II) wherein R¹¹ is —F. In some embodiments is a compound offormula (II) wherein R¹¹ is C₁₋₆ haloalkyl. In some embodiments is acompound of formula (II) wherein R¹¹ is —CF₃. In some embodiments is acompound of formula (II) wherein R¹¹ is —N(R⁶)₂ or —C₁₋₆alkyl-N(R⁶)₂. Insome embodiments is a compound of formula (II) wherein R¹¹ is —N(R⁶)₂.In some embodiments is a compound of formula (II) wherein R¹¹ is —NH₂.In some embodiments is a compound of formula (II) wherein R¹¹ is—C₁₋₆alkyl-N(R⁶)₂. In some embodiments is a compound of formula (II)wherein R¹¹ is —CH₂NH₂.

In another aspect is a compound of formula (III) having the structure:

wherein:

-   R² is independently halo, C₁₋₆alkyl, or C₁₋₆haloalkyl;-   R^(4a) and R^(4b) are each independently hydrogen, halo, C₁₋₆alkyl,    or C₁₋₆haloalkyl; or R^(4a) and R^(4b), together with the carbon to    which they are both attached, form a cycloalkyl;-   each R⁶ is independently hydrogen or C₁₋₆alkyl;-   each R¹² is independently —OH, —CN, halo, C₁₋₆alkyl, C₁₋₆haloalkyl,    C₁₋₆alkoxy, C₁₋₆haloalkoxy, —N(R⁶)₂, —C₁₋₆alkyl-N(R⁶)₂, —C(O)R⁶,    —C(O)OR⁶, —C(O)N(R⁶)₂, aryl, aralkyl, cycloalkyl, heterocyclyl, or    heteroaryl; and-   n is 0, 1, 2, 3, or 4;-   as an individual stereoisomer, enantiomer or tautomer thereof or a    mixture thereof;-   or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In some embodiments is a compound of formula (III) wherein R² is halo.In some embodiments is a compound of formula (III) wherein R² is —F. Insome embodiments is a compound of formula (III) wherein R² is —Cl. Insome embodiments is a compound of formula (III) wherein R² is C₁₋₆alkyl.In some embodiments is a compound of formula (III) wherein R² is —CH₃.In some embodiments is a compound of formula (III) wherein R^(4a) isC₁₋₆alkyl. In some embodiments is a compound of formula (III) whereinR^(4a) is —CH₃. In some embodiments is a compound of formula (III)wherein R^(4b) is hydrogen. In some embodiments is a compound of formula(III) wherein each R¹² is independently —OH, —CN, halo, C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, —N(R⁶)₂, —C₁₋₆alkyl-N(R⁶)₂,—C(O)R⁶, —C(O)OR⁶, or —C(O)N(R⁶)₂. In some embodiments is a compound offormula (III) wherein each R¹² is independently halo, C₁₋₆ alkyl,C₁₋₆haloalkyl, —N(R⁶)₂, —C₁₋₆alkyl-N(R⁶)₂, or —C(O)N(R⁶)₂. In someembodiments is a compound of formula (III) wherein R¹² is halo. In someembodiments is a compound of formula (III) wherein R¹² is —F. In someembodiments is a compound of formula (III) wherein R¹² is —Cl. In someembodiments is a compound of formula (III) wherein R¹² is C₁₋₆haloalkyl.In some embodiments is a compound of formula (III) wherein R¹² is —CF₃.In some embodiments is a compound of formula (III) wherein R¹² is—N(R⁶)₂ or —C₁₋₆alkyl-N(R⁶)₂. In some embodiments is a compound offormula (III) wherein R¹² is —N(R⁶)₂. In some embodiments is a compoundof formula (III) wherein R¹² is —NH₂. In some embodiments is a compoundof formula (III) wherein R¹² is —C₁₋₆alkyl-N(R⁶)₂. In some embodimentsis a compound of formula (III) wherein R¹² is —CH₂NH₂. In someembodiments is a compound of formula (III) wherein n is 1. In someembodiments is a compound of formula (III) wherein n is 0.

In another aspect is a compound of formula (IV) having the structure:

wherein:

is heterocyclyl;

-   R² is independently hydrogen, halo, C₁₋₆alkyl, or C₁₋₆haloalkyl;-   R^(4a) and R^(4b) are each independently hydrogen, halo, C₁₋₆alkyl,    or C₁₋₆haloalkyl; or R^(4a) and R^(4b), together with the carbon to    which they are both attached, form a cycloalkyl;-   each R⁶ is independently hydrogen or C₁₋₆alkyl;-   R¹¹ is halo, C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁶)₂, —C₁₋₆alkyl-N(R⁶)₂,    or —C(O)N(R⁶)₂;-   each R¹² is independently —OH, —CN, halo, C₁₋₆alkyl, C₁₋₆haloalkyl,    C₁₋₆alkoxy, C₁₋₆haloalkoxy, —N(R⁶)₂, —C₁₋₆alkyl-N(R⁶)₂, —C(O)R⁶,    —C(O)OR⁶, —C(O)N(R⁶)₂, aryl, aralkyl, cycloalkyl, heterocyclyl, or    heteroaryl; and-   n is 0, 1, 2, 3, or 4;-   as an individual stereoisomer, enantiomer or tautomer thereof or a    mixture thereof;-   or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In some embodiments is a compound of formula (IV) wherein R² ishydrogen. In some embodiments is a compound of formula (IV) wherein R²is halo. In some embodiments is a compound of formula (IV) wherein R² is—F. In some embodiments is a compound of formula (IV) wherein R² is —Cl.In some embodiments is a compound of formula (IV) wherein R² is C₁₋₆alkyl. In some embodiments is a compound of formula (IV) wherein R² is—CH₃. In some embodiments is a compound of formula (IV) wherein R^(4a)is C₁₋₆alkyl. In some embodiments is a compound of formula (IV) whereinR^(4a) is —CH₃. In some embodiments is a compound of formula (IV)wherein R^(4b) is hydrogen. In some embodiments is a compound of formula(IV) wherein each R¹² is independently —OH, —CN, halo, C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —N(R⁶)₂, —C₁₋₆alkyl-N(R⁶)₂,—C(O)R⁶, —C(O)OR⁶, or —C(O)N(R⁶)₂. In some embodiments is a compound offormula (IV) wherein each R¹² is independently halo, C₁₋₆alkyl, —N(R⁶)₂,—C₁₋₆alkyl-N(R⁶)₂, or C₁₋₆haloalkyl. In some embodiments is a compoundof formula (IV) wherein n is 1. In some embodiments is a compound offormula (IV) wherein n is 0. In some embodiments is a compound offormula (IV) wherein R¹¹ is halo. In some embodiments is a compound offormula (IV) wherein R¹¹ is —F. In some embodiments is a compound offormula (IV) wherein R¹¹ is C₁₋₆alkyl. In some embodiments is a compoundof formula (IV) wherein R¹¹ is —CH₃. In some embodiments is a compoundof formula (IV) wherein R¹¹ is —N(R⁶)₂ or —C₁₋₆alkyl-N(R⁶)₂. In someembodiments is a compound of formula (IV) wherein R¹¹ is —N(R⁶)₂. Insome embodiments is a compound of formula (IV) wherein R¹¹ is —NH₂. Insome embodiments is a compound of formula (IV) wherein R¹¹ is—C₁₋₆alkyl-N(R⁶)₂. In some embodiments is a compound of formula (IV)wherein R¹ is —CH₂NH₂. In some embodiments is a compound of formula (IV)wherein

is piperidine. In some embodiments is a compound of formula (IV) wherein

is piperazine.

In some embodiments is a compound selected from:(R)-1-benzyl-N-(9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-2-yl)-1H-pyrazole-4-carboxamide;(R)—N-(1-(3-aminobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;(R)—N-(1-(2-aminobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;and(R)-1-(3-aminobenzyl)-N-(9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-2-yl)-1H-pyrazole-4-carboxamide;or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In some embodiments is a compound having the structure:(R)-9-methyl-N-(1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In some embodiments is a compound selected from:(R)-9-methyl-6-oxo-N-(1-(4-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;(R)—N-(1-(2,4-difluorobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;and(R)—N-(1-benzyl-1H-pyrazol-4-yl)-5-chloro-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In some embodiments is a compound having the structure:(R)—N-(1-(4-(aminomethyl)benzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In some embodiments is a compound having the structure:(R)—N-(1-(4-(aminomethyl)benzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamidehydrochloride salt; or a pharmaceutically acceptable solvate or prodrugthereof.

In some embodiments is a compound having the structure:(R)—N-(1-(4-aminobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In some embodiments is a compound having the structure:

(R)—N-(1-(4-aminobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamidehydrochloride salt; or a pharmaceutically acceptable solvate or prodrugthereof.

In some embodiments is a compound having the structure:(R)—N-(2-carbamoylphenyl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another aspect described herein, are pharmaceutical compositionscomprising a pharmaceutically acceptable excipient and a compounddescribed herein as described above, as an individual stereoisomer,enantiomer or tautomer thereof or a mixture thereof; or apharmaceutically acceptable salt, solvate, or prodrug thereof.

In another aspect is a method of treating a disease or conditionassociated with RSK activity in a mammal, wherein the method comprisesadministering to the mammal a therapeutically effective amount of acompound as described herein, as an individual stereoisomer, enantiomeror tautomer thereof or a mixture thereof; or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof. In some embodiments, thedisease or condition associated with RSK activity in a mammal is cancer.In some embodiments, the cancer is breast cancer, prostate cancer, lungcancer, brain cancer, skin cancer, bone cancer, ovarian cancer, multiplemyeloma or leukemia. In some embodiments is a method of treating adisease or condition associated with RSK activity in a mammal, whereinthe method comprises administering to the mammal a therapeuticallyeffective amount of a compound as described herein, as an individualstereoisomer, enantiomer or tautomer thereof or a mixture thereof; or apharmaceutically acceptable salt, solvate, or prodrug thereof; furthercomprising the administration of a second therapeutic agent. In someembodiments, the second therapeutic agent is a chemotherapeutic agent,hormonal therapeutic agent, or an immunotherapeutic agent. In someembodiments, the second therapeutic agent is a poly ADP-ribosepolymerase (PARP) inhibitor, STAT 3 inhibitor, Janus Kinase inhibitor,or EGFR inhibitor. In some embodiments, the second therapeutic agent isa chemotherapeutic agent (small molecule or antibody). In someembodiments, the second therapeutic agent is paclitaxel. In someembodiments, the second therapeutic agent is methotrexate. In someembodiments, the second therapeutic agent is 5-fluorouracil. In someembodiments, the second therapeutic agent is adriamycin.

In some embodiments, the method further comprises the administration ofradiation therapy.

In another aspect described herein are assays to determine theeffectiveness of a compound described herein in inhibiting RSK activityin a cell-based assay.

In another aspect described herein is a method of inhibiting an activityof RSK, comprising contacting in vitro RSK with an amount of a compoundeffective to inhibit the activity of RSK wherein the compound isselected from the compounds described herein, or a pharmaceuticallyacceptable salt thereof, as described herein.

In another aspect described herein is a method of inhibiting an activityof RSK comprising contacting in a cell RSK with an amount of a compoundeffective to inhibit the activity of RSK wherein the compound isselected from the compounds described herein, or a pharmaceuticallyacceptable salt thereof, as described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the percent survival of MDA-MB-231 breast cancer cells inthe Alamar blue assay when treated with varying concentrations ofcompounds described herein.

FIG. 2 depicts the percent survival of MDA-MB-468 breast cancer cells inthe Alamar blue assay when treated with varying concentrations ofcompounds described herein.

FIG. 3 depicts the percent survival of SUM149 breast cancer cells in theAlamar blue assay when treated with varying concentrations of compoundsdescribed herein.

FIG. 4 depicts the percent survival of 4T1 breast cancer cells in theAlamar blue assay when treated with varying concentrations of compoundsdescribed herein.

FIG. 5 depicts the percent survival of MDA-MB-231 breast cancer cells inthe crystal violet assay when treated with varying concentrations ofcompounds described herein.

FIG. 6 depicts the percent survival of MDA-MB-468 breast cancer cells inthe crystal violet assay when treated with varying concentrations ofcompounds described herein.

FIG. 7 depicts the percent survival of SUM149 breast cancer cells in thecrystal violet assay when treated with varying concentrations ofcompounds described herein.

FIG. 8 depicts the percent survival of 4T1 breast cancer cells in thecrystal violet assay when treated with varying concentrations ofcompounds described herein.

FIG. 9A depicts the percent survival of 4T1 breast cancer cells in thesoft agar growth inhibition assay when treated with varyingconcentrations of either Compound 15 or Compound 16. FIG. 9B depicts thepercent survival of MDA-MB-231, MDA-MB-468 or 4T1 cells grown in softagar when the cells were treated with varying concentrations of Compound25.

FIGS. 10A and 10B depict cell signaling inhibition in MDA-MB-231 cellstreated with compounds 18 and 25 wherein loss of signaling is measuredby the reduction in the intensity of P-YB-1.

FIGS. 11A and 11B depict cell signaling inhibition in MDA-MB-231 cellstreated with compounds 16 and 18 wherein loss of signaling is measuredby the reduction in the intensity of P-YB-1.

FIG. 12 depicts PARP cleavage induced by compound 25 (5 days oftreatment, single dose) in TNBC models.

FIG. 13 depicts the effect of combination treatment with compound 18 andpaclitaxel on monolayer growth in MDA-MB-231 cells.

FIG. 14A depicts the effect of compounds 16 and 18 on immune recognitionby inducing the MHC-II gene HLA-DRA in MDA-MB-231 cells. FIG. 14A alsodepicts a lack of effect compound 16 and 18 have on the master regulatorCIITA.

FIG. 14B depicts the effect of compound 18 on immune recognition byinducing the MHC-II gene HLA-DRA in JIMT-1 cells. FIG. 14B also depictsa lack of effect compound 18 had on the master regulator CIITA.

FIG. 14C depicts the effect of compound 16 and 18 on immune recognitionby reducing CD274, the gene that encodes PDL-1 in MDA-MB-231 cells.

FIG. 14D depicts the effect of compound 18 on immune recognition byreducing CD274, the gene that encodes PDL-1 in JIMT-1 cells.

FIG. 15 depicts the effect of compound 25 on cell signaling inMDA-MB-231 xenografts after three days of treatment.

FIGS. 16A and 16B depict the effect as well as quantification ofcompound 25 on cell signaling in MDA-MB-231 xenografts after 21 days oftreatment.

FIG. 17 depicts the percent survival of human CD34+ cells when treatedwith varying concentrations of compounds described herein.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated:

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Formyl” refers to the —C(O)H radical.

“Hydroxy” refers to the —OH radical.

“Nitro” refers to the —NO₂ radical.

“Oxo” refers to the ═O substituent.

“Thioxo” refers to the ═S substituent.

“Trifluoromethyl” refers to the —CF₃ radical.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to twelve carbon atoms, preferably one toeight carbon atoms, more preferably one to six carbon atoms, and whichis attached to the rest of the molecule by a single bond, e.g., methyl,ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like.When specifically stated in the specification, an alkyl group may beoptionally substituted by one of the following groups: alkyl, alkenyl,halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl,heteroaryl, oxo, trimethylsilanyl, —OR²⁰, —OC(O)—R²⁰, —N(R²⁰)₂,—C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂, —N(R²⁰)C(O)OR²², —N(R²⁰)C(O)R²²,—N(R²⁰)S(O)_(p)R²² (where p is 1 to 2), —S(O)_(p)OR²² (where p is 1 to2), —S(O)_(t)R²² (where t is 0 to 2), and —S(O)_(p)N(R²⁰)₂ (where p is 1to 2) where each R²⁰ is independently hydrogen, alkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl; and each R²² is alkyl,haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group orlinking two parts of the molecule, consisting solely of carbon andhydrogen, containing no unsaturation and having from one to twelvecarbon atoms, e.g., methylene, ethylene, propylene, n-butylene, and thelike. The alkylene chain may optionally contain one or more heteroatomswherein a carbon in the alkylene chain is replaced with a heteroatomselected from oxygen, nitrogen or sulfur. The alkylene chain is attachedto the rest of the molecule through a single bond and to the radicalgroup through a single bond or is attached to two parts of the moleculethrough a single bond at each point of attachment. When specificallystated in the specification, an alkylene chain may be optionallysubstituted by one of the following groups: alkyl, alkenyl, halo,haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl,oxo, trimethylsilanyl, —OR²⁰, —OC(O)—R²⁰, —N(R²⁰)₂, —C(O)R²⁰, —C(O)OR²⁰,—C(O)N(R²⁰)₂, —N(R²⁰)C(O)OR²², —N(R²⁰)C(O)R²², —N(R²⁰)S(O)_(p)R²² (wherep is 1 to 2), —S(O)_(p)OR²² (where p is 1 to 2), —S(O)_(t)R²² (where tis 0 to 2), and —S(O)_(p)N(R²⁰)₂ (where p is 1 to 2) where each R²⁰ isindependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl; and each R²² is alkyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl.

“Aryl” refers to a hydrocarbon ring system radical comprising hydrogen,6 to 18 carbon atoms and at least one aromatic ring. For purposes ofthis invention, the aryl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, which may included fused orbridged ring systems. Aryl radicals include, but are not limited to,aryl radicals derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene,fluorene, as-indacene, s-indacene, indane, indene, naphthalene,phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Whenspecifically stated in the specification, an aryl group may beoptionally substituted by one or more substituents independentlyselected from the group consisting of alkyl, alkenyl, halo, haloalkyl,haloalkenyl, cyano, nitro, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R²¹—OR²⁰,—R²¹—OC(O)—R²⁰, —R²¹—N(R²⁰)₂, —R²¹—C(O)R²⁰, —R²¹—C(O)OR²⁰,—R²¹—C(O)N(R²⁰)₂, —R²¹—N(R²⁰)C(O)OR²², —R²¹—N(R²⁰)C(O)R²²,—R²¹—N(R²⁰)S(O)_(p)R²² (where p is 1 to 2), —R²¹—N═C(OR²⁰)R²⁰,—R²¹—S(O)_(p)OR²² (where p is 1 to 2), —R²¹—S(O)_(t)R²² (where t is 0 to2), and —R²¹—S(O)_(p)N(R²⁰)₂ (where p is 1 to 2) where each R²⁰ isindependently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl; each R²¹ is independently a direct bond or a straightor branched alkylene chain; and each R²² is alkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Aralkyl” refers to a radical of the formula —R_(b)—R_(c) where R_(b) isan alkylene chain as defined above and R_(c) is one or more arylradicals as defined above, for example, benzyl, diphenylmethyl and thelike. When specifically stated in the specification, the alkylene chainpart of the aralkyl radical may be optionally substituted as describedabove for an optionally substituted alkylene chain. When specificallystated in the specification, the aryl part of the aralkyl radical may beoptionally substituted as described above for an optionally substitutedaryl group.

“Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which may include fused or bridged ring systems, having from three tofifteen carbon atoms, preferably having from three to ten carbon atoms,and which is saturated or unsaturated and attached to the rest of themolecule by a single bond. Monocyclic radicals include, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptly, andcyclooctyl. Polycyclic radicals include, for example, adamantyl,norbornyl, decalinyl, and the like. When specifically stated in thespecification, a cycloalkyl group may be optionally substituted by oneor more substituents independently selected from the group consisting ofalkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, nitro, oxo, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, heteroarylalkyl, —R²¹—OR²⁰, —R²¹—OC(O)—R²⁰, —R²¹—N(R²⁰)₂,—R²¹—C(O)R²⁰, —R²¹—C(O)OR²⁰, —R²¹—C(O)N(R²⁰)₂, —R²¹—N(R²⁰)C(O)OR²²,—R²¹—N(R²⁰)C(O)R²², —R²¹—N(R²⁰)S(O)_(p)R²² (where p is 1 to 2),—R²¹—N═C(OR²⁰⁾R²⁰, —R²¹—S(O)_(p)OR²² (where p is 1 to 2),—R²¹—S(O)_(t)R²² (where t is 0 to 2), and —R²¹—S(O)_(p)N(R²⁰)₂ (where pis 1 to 2) where each R²⁰ is independently hydrogen, alkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R²¹ isindependently a direct bond or a straight or branched alkylene chain;and each R²² is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Cycloalkylalkyl” refers to a radical of the formula —R_(b)R_(g) whereR_(b) is an alkylene chain as defined above and R_(g) is a cycloalkylradical as defined above. When specifically stated in the specification,the alkylene chain and/or the cycloalkyl radical may be optionallysubstituted as defined above for optionally substituted alkylene chainand optionally substituted cycloalkyl.

“Halo” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl,1-bromomethyl-2-bromoethyl, and the like. The alkyl part of thehaloalkyl radical may be optionally substituted as defined above for analkyl group.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringradical which consists of two to twelve carbon atoms and from one to sixheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur. Unless stated otherwise specifically in the specification, theheterocyclyl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heterocyclylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized; and the heterocyclyl radical may be partially or fullysaturated. Examples of such heterocyclyl radicals include, but are notlimited to, dioxolanyl, dioxinyl, thienyl[1,3]dithianyl,decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl,isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl,piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,quinuclidinyl, thiazolidinyl, 1,2,4-thiadiazol-5(4H)-ylidene,tetrahydrofuryl, trioxanyl, trithianyl, triazinanyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. When specifically stated in thespecification, a heterocyclyl group may be optionally substituted by oneor more substituents selected from the group consisting of alkyl,alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo, thioxo, nitro, aryl,aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,heteroaryl, heteroarylalkyl, —R²¹—OR²⁰, —R²¹—OC(O)—R²⁰, —R²¹—N(R²⁰)₂,—R²¹—C(O)R²⁰, —R²¹—C(O)OR²⁰, —R²¹—C(O)N(R²⁰)₂, —R²¹—N(R²⁰)C(O)OR²²,—R²¹—N(R²⁰)C(O)R²², —R²¹—N(R²⁰)S(O)_(p)R²² (where p is 1 to 2),—R²¹—N═C(OR²⁰)R²⁰, —R²¹—S(O)_(p)OR²² (where p is 1 to 2),—R²¹—S(O)_(t)R²² (where t is 0 to 2), and —R²¹—S(O)_(p)N(R²⁰)₂ (where pis 1 to 2) where each R²⁰ is independently hydrogen, alkyl, alkenyl,haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl; each R²¹ isindependently a direct bond or a straight or branched alkylene chain;and each R²² is alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl orheteroarylalkyl.

“N-heterocyclyl” refers to a heterocyclyl radical as defined abovecontaining at least one nitrogen. The point of attachment of theN-heterocyclyl to the rest of the molecule can be through a nitrogenatom or a carbon atom in the N-heterocyclyl. When specifically stated inthe specification, an N-heterocyclyl radical may be optionallysubstituted as described above for an optionally substitutedheterocyclyl radical.

“Heterocyclylalkyl” refers to a radical of the formula —R_(b)R_(h) whereR_(b) is an alkylene chain as defined above and R_(h) is a heterocyclylradical as defined above, and if the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkyl radical at the nitrogen atom. When specifically stated in thespecification, the alkylene chain of the heterocyclylalkyl radical maybe optionally substituted as defined above for an optionally substitutedalkyene chain. When specifically stated in the specification, theheterocyclyl part of the heterocyclylalkyl radical may be optionallysubstituted as defined above for an optionally substituted heterocyclylgroup.

“Heteroaryl” refers to a 5- to 14-membered ring system radicalcomprising hydrogen atoms, one to thirteen carbon atoms, one to sixheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur, and at least one aromatic ring. For purposes of this invention,the heteroaryl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heteroarylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized. Examples include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzthiazolyl, benzindolyl, benzodioxolyl,benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,benzoxazolinonyl, benzimidazolthionyl, carbazolyl, cinnolinyl,dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl,imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl,isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl,oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl,1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl,1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl,phthalazinyl, pteridinyl, pteridinonyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyridinonyl, pyrazinyl, pyrimidinyl, pryrimidinonyl,pyridazinyl, pyrrolyl, pyrido[2,3-d]pyrimidinonyl, quinazolinyl,quinazolinonyl, quinoxalinyl, quinoxalinonyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl,thieno[3,2-d]pyrimidin-4-onyl, thieno[2,3-d]pyrimidin-4-onyl, triazolyl,tetrazolyl, triazinyl, and thiophenyl (i.e. thienyl). When specificallystated in the specification, a heteroaryl group may be optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, alkenyl, halo, haloalkyl, haloalkenyl, cyano, oxo,thioxo, nitro, thioxo, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —R²¹—OR²⁰,—R²¹—OC(O)—R²⁰, —R²¹—N(R²⁰)₂, —R²¹—C(O)R²⁰, —R²¹—C(O)OR²⁰,—R²¹—C(O)N(R²⁰)₂, —R²¹—N(R²⁰)C(O)OR²², —R²¹—N(R²⁰)C(O)R²²,—R²¹—N(R²⁰)S(O)_(p)R²² (where p is 1 to 2), —R²¹—N═C(OR²⁰)R²⁰,—R²¹—S(O)_(p)OR²² (where p is 1 to 2), —R²¹—S(O)_(t)R²² (where t is 0 to2), and —R²¹—S(O)_(p)N(R²⁰)₂ (where p is 1 to 2) where each R²⁰ isindependently hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,heteroaryl or heteroarylalkyl; each R²¹ is independently a direct bondor a straight or branched alkylene chain; and each R²² is alkyl,alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen. The point of attachment of theN-heteroaryl to the rest of the molecule can be through a nitrogen atomor a carbon atom in the N-heteroaryl. When specifically stated in thespecification, an N-heteroaryl radical may be optionally substituted asdescribed above for an optionally substituted heteroaryl radical.

“Heteroarylalkyl” refers to a radical of the formula —R_(b)R_(i) whereR_(b) is an alkylene chain as defined above and R_(i) is a heteroarylradical as defined above. When specifically stated in the specification,the heteroaryl part of the heteroarylalkyl radical may be optionallysubstituted as defined above for an optionally substituted heteroarylgroup. When specifically stated in the specification, the alkylene chainpart of the heteroarylalkyl radical may be optionally substituted asdefined above for an optionally substituted alkylene chain.

“Prodrugs” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound of the invention. Thus, the term “prodrug” refers to ametabolic precursor of a compound described herein that ispharmaceutically acceptable. A prodrug may be inactive when administeredto a subject in need thereof, but is converted in vivo to an activecompound of the invention. Prodrugs are typically rapidly transformed invivo to yield the parent compound described herein, for example, byhydrolysis in blood. The prodrug compound often offers advantages ofsolubility, tissue compatibility or delayed release in a mammalianorganism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24(Elsevier, Amsterdam)). A discussion of prodrugs is provided in Higuchi,T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. SymposiumSeries, Vol. 14, and in Bioreversible Carriers in Drug Design, Ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987, both of which are incorporated in full by reference herein.

The term “prodrug” is also meant to include any covalently bondedcarriers, which release the active compound of the invention in vivowhen such prodrug is administered to a mammalian subject. In someembodiments, prodrugs of a compound described herein are prepared bymodifying functional groups present in the compound in such a way thatthe modifications are cleaved, either in routine manipulation or invivo, to the parent compound described herein. Prodrugs includecompounds described herein wherein a hydroxy, amino or mercapto group isbonded to any group that, when the prodrug of the compound describedherein is administered to a mammalian subject, cleaves to form a freehydroxy, free amino or free mercapto group, respectively. Examples ofprodrugs include, but are not limited to, acetate, formate and benzoatederivatives of alcohol or amide derivatives of amine functional groupsin the compounds described herein and the like.

The invention disclosed herein is also meant to encompass allpharmaceutically acceptable compounds of formula (I) beingisotopically-labelled by having one or more atoms replaced by an atomhaving a different atomic mass or mass number. Examples of isotopes thatcan be incorporated into the disclosed compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, andiodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P,³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. These radiolabelledcompounds could be useful to help determine or measure the effectivenessof the compounds, by characterizing, for example, the site or mode ofaction on the RSK, or binding affinity to pharmacologically importantsite of action on the RSK. Certain isotopically-labelled compounds offormula (I), for example, those incorporating a radioactive isotope, areuseful in drug and/or substrate tissue distribution studies. Theradioactive isotopes tritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, areparticularly useful for this purpose in view of their ease ofincorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labeled compoundsof formula (I) can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed in the Examples and Preparations as set out below using anappropriate isotopically-labeled reagent in place of the non-labeledreagent previously employed.

The invention disclosed herein is also meant to encompass the in vivometabolic products of the disclosed compounds. Such products may resultfrom, for example, the oxidation, reducation, hydrolysis, amidation,esterification, and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising contacting a compound of this inventionwith a mammal for a period of time sufficient to yield a metabolicproduct thereof. Such products are typically are identified byadministering a radiolabelled compound described herein in a detectabledose to an animal, such as rat, mouse, guinea pig, monkey, or to human,allowing sufficient time for metabolism to occur, and isolating itscoversion products from the urine, blood or other biological samples.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Mammal” includes humans and both domestic animals such as laboratoryanimals and household pets, (e.g., cats, dogs, swine, cattle, sheep,goats, horses, rabbits), and non-domestic animals such as wildelife andthe like.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution (“unsubstituted). When a functional group is described as“optionally substituted,” and in turn, substitutents on the functionalgroup are also “optionally substituted” and so on, for the purposes ofthis invention, such iterations are limited to five, preferably suchiterations are limited to two.

“Pharmaceutically acceptable carrier, diluent or excipient” includeswithout limitation any adjuvant, carrier, excipient, glidant, sweeteningagent, diluent, preservative, dye/colorant, flavor enhancer, surfactant,wetting agent, dispersing agent, suspending agent, stabilizer, isotonicagent, solvent, or emulsifier which has been approved by the UnitedStates Food and Drug Administration as being acceptable for use inhumans or domestic animals.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as, but are not limited to,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as, but not limitedto, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid, lactobionic acid, lauric acid,maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonicacid, mucic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroaceticacid, undecylenic acid, and the like.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as ammonia,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, diethanolamine, ethanolamine, deanol,2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, benethamine, benzathine, ethylenediamine, glucosamine,methylglucamine, theobromine, triethanolamine, tromethamine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. Particularly preferred organic bases are isopropylamine,diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, cholineand caffeine.

Often crystallizations produce a solvate of the compound describedherein. As used herein, the term “solvate” refers to an aggregate thatcomprises one or more molecules of a compound described herein with oneor more molecules of solvent. In some embodiments, the solvent is water,in which case the solvate is a hydrate. Alternatively, in someembodiments, the solvent is an organic solvent. Thus, the compounds ofthe present invention may exist as a hydrate, including a monohydrate,dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and thelike, as well as the corresponding solvated forms. In some embodiments,the compound described herein is a true solvate, while in other cases,the compound described herein may merely retain adventitious water or bea mixture of water plus some adventitious solvent.

A “pharmaceutical composition” refers to a formulation of a compounddescribed herein and a medium generally accepted in the art for thedelivery of the biologically active compound to mammals, e.g., humans.Such a medium includes all pharmaceutically acceptable carriers,diluents or excipients therefor.

“Therapeutically effective amount” refers to that amount of a compounddescribed herein which, when administered to a mammal, preferably ahuman, is sufficient to effect treatment, as defined below, ofRSK-mediated disease or condition in the mammal, preferably a human. Theamount of a compound described herein which constitutes a“therapeutically effective amount” will vary depending on the compound,the condition and its severity, the manner of administration, and theage of the mammal to be treated, but can be determined routinely by oneof ordinary skill in the art having regard to his own knowledge and tothis disclosure.

“Treating” or “treatment” as used herein covers the treatment of thedisease or condition of interest in a mammal, preferably a human, havingthe disease or condition of interest, and includes:

(a) preventing the disease or condition from occurring in a mammal, inparticular, when such mammal is predisposed to the condition but has notyet been diagnosed as having it;

(b) inhibiting the disease or condition, i.e., arresting itsdevelopment;

(c) relieving (or ameliorating) the disease or condition, i.e., causingregression of the disease or condition; or

(d) relieving (or ameliorating) the symptoms resulting from the diseaseor condition, e.g., relieving cancer symptoms without addressing theunderlying disease or condition.

As used herein, the terms “disease” and “condition” may be usedinterchangeably or may be different in that the particular malady orcondition may not have a known causative agent (so that etiology has notyet been worked out) and it is therefore not yet recognized as a diseasebut only as an undesirable condition or syndrome, wherein a more or lessspecific set of symptoms have been identified by clinicians.

The compounds described herein, or their pharmaceutically acceptablesalts may contain one or more asymmetric centres and may thus give riseto enantiomers, diastereomers, and other stereoisomeric forms that maybe defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms. In some embodiments, optically active (+) and (−), (R)- and (S)-,or (D)- and (L)- isomers are prepared using chiral synthons or chiralreagents, or resolved using conventional techniques, for example,chromatography and fractional crystallisation. Conventional techniquesfor the preparation/isolation of individual enantiomers include chiralsynthesis from a suitable optically pure precursor or resolution of theracemate (or the racemate of a salt or derivative) using, for example,chiral high pressure liquid chromatography (HPLC). When the compoundsdescribed herein contain olefinic double bonds or other centres ofgeometric asymmetry, and unless specified otherwise, it is intended thatthe compounds include both E and Z geometric isomers. Likewise, alltautomeric forms are also intended to be included.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes enantiomers,which refers to two stereoisomers whose molecules are nonsuperimposablemirror images of one another. See, for example, Smith, M. B. and J.March, March's Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, current edition (Wiley), for a detailed description of thestructure and properties of enantiomers and stereoisomers.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The present invention includestautomers of any said compounds.

The use of parentheses and brackets in substituent groups is used hereinto conserve space. Accordingly, the use of parenthesis in a substituentgroup indicates that the group enclosed within the parentheses isattached directly to the atom preceding the parenthesis. The use ofbrackets in a substituent group indicates that the group enclosed withinthe brackets is also attached directly to the atom preceding theparenthesis.

The chemical naming protocol and structure diagrams used herein are amodified form of the I.U.P.A.C. nomenclature system, using ChemBioDrawUltra Version 12.0 software program, wherein the compounds describedherein are named herein as derivatives of a central core structure,e.g., the carboxamide structure. For complex chemical names employedherein, a substituent group is named before the group to which itattaches. For example, cyclopropylethyl comprises an ethyl backbone withcyclopropyl substituent. In chemical structure diagrams, all bonds areidentified, except for some carbon atoms, which are assumed to be bondedto sufficient hydrogen atoms to complete the valency.

“Enantiomers” refer to asymmetric molecules that can exist in twodifferent isomeric forms which have different configurations in space.Other terms used to designate or refer to enantiomers include“stereoisomers” (because of the different arrangement or stereochemistryaround the chiral center; although all enantiomers are stereoisomers,not all stereoisomers are enantiomers) or “optical isomers” (because ofthe optical activity of pure enantiomers, which is the ability ofdifferent pure enantiomers to rotate plane-polarized light in differentdirections).

The designations, “R” and “S”, for the absolute configuration of anenantiomer of a compound described herein may appear as a prefix or as asuffix in the name of the compound; they may or may not be separatedfrom the enantiomer name by a hyphen; they may or may not be hyphenated;and they may or may not be surrounded by parentheses.

“Resolution” or “resolving” when used in reference to a racemic compoundor a racemic mixture of a compound described herein refers to theseparation of the racemic compound or a racemic mixture into its twoenantiomeric forms (i.e., (+) and (−); (R) and (S) forms).

“Enantiomeric excess” or “ee” as used herein refers to a product whereinone enantiomer is present in excess of the other, and is defined as theabsolute difference in the mole fraction of each enantiomer.Enantiomeric excess is typically expressed as a percentage of anenantiomer present in a mixture relative to the other enantiomer. Forpurposes of this invention, the (S)-enantiomer of a compound prepared bythe methods disclosed herein is considered to be “substantially free” ofthe corresponding (R)-enantiomer when the (S)-enantiomer is present inenantiomeric excess of greater than 80%, preferably greater than 90%,more preferably greater than 95% and most preferably greater than 99%.

Embodiments of the Invention

Of the various aspects of the invention set forth above in the Summaryof the Invention, certain embodiments are preferred.

Compounds

Of the compounds of formula (I) as described above in the Summary of theInvention, one embodiment is the compounds of formula (I) wherein R¹ isR⁵—C(O)N(R⁶)—, i.e., a compound having the formula (Ia):

wherein:

-   n is 1 or 2;-   A is —N═ or —C(R³)═;-   B is —O—, —N(R⁴)—, or —S(O)_(t) (where t is 0, 1 or 2)-;-   E is —N═ or —C(R³)═;-   each R² is independently hydrogen, alkyl, halo, haloalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;-   or two R², together with the adjacent carbons to which they are    attached, form a fused optionally substituted 6-membered    N-heterocyclyl;-   each R³ is independently hydrogen, alkyl, haloalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl or optionally    substituted heteroarylalkyl;-   R⁴ is hydrogen, alkyl, haloalkyl, optionally substituted aryl or    optionally substituted aralkyl;-   or R⁴, together with the nitrogen to which it is attached, and a R²,    together with the adjacent carbon to which it is attached, together    form a fused 6-membered N-heterocyclyl of the following structure:

-   -   where        indicates the point of fusion and R^(4a), R^(4b), R^(4c), and        R^(4d) are each independently hydrogen, alkyl, halo or haloalkyl        or R^(4a) and R^(4b), together with the carbon to which they are        both attached, form a cycloalkyl or R^(4c) and R^(4d), together        with the carbon to which they are both attached, form a        cycloalkyl, and the remaining R², if present, is selected from        hydrogen, alkyl, halo or haloalkyl;

-   R⁵ is optionally substituted aryl or optionally substituted    N-heteroaryl; and

-   R⁶ is hydrogen, alkyl, haloalkyl, optionally substituted aryl or    optionally substituted aralkyl.

Of this embodiment, an embodiment is a compound of formula (Ia) whereinA is —C(R³)═, i.e., a compound having the formula (Ia1):

wherein:

-   n is 1 or 2;-   B is —O—, —N(R⁴)—, or —S(O)_(t) (where t is 0, 1 or 2)-;-   E is —N═ or —C(R³)═;-   each R² is independently hydrogen, alkyl, halo, haloalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;-   or two R², together with the adjacent carbons to which they are    attached, form a fused optionally substituted 6-membered    N-heterocyclyl;-   each R³ is independently hydrogen, alkyl, haloalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl or optionally    substituted heteroarylalkyl;-   R⁴ is hydrogen, alkyl, haloalkyl, optionally substituted aryl or    optionally substituted aralkyl;-   or R⁴, together with the nitrogen to which it is attached, and a R²,    together with the adjacent carbon to which it is attached, together    form a fused 6-membered N-heterocyclyl of the following structure:

-   -   where        indicates the point of fusion and R^(4a), R^(4b), R^(4c), and        R^(4d) are each independently hydrogen, alkyl, halo or haloalkyl        or R^(4a) and R^(4b), together with the carbon to which they are        both attached, form a cycloalkyl or R^(4c) and R^(4d), together        with the carbon to which they are both attached, form a        cycloalkyl, and the remaining R², if present, is selected from        hydrogen, alkyl, halo or haloalkyl;

-   R⁵ is optionally substituted aryl or optionally substituted    N-heteroaryl; and

-   R⁶ is hydrogen, alkyl, haloalkyl, optionally substituted aryl or    optionally substituted aralkyl.

Of this embodiment, an embodiment is a compound of formula (Ia1)wherein:

-   n is 1 or 2;-   B is —N(R⁴)—;-   E is —N═ or —C(R³)═;-   each R² is independently hydrogen, halo, alkyl, haloalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;-   or two R², together with the adjacent carbons to which they are    attached, form a fused optionally substituted 6-membered    N-heterocyclyl;-   each R³ is independently hydrogen, alkyl, haloalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl or optionally    substituted heteroarylalkyl;-   R⁴ is hydrogen, alkyl, haloalkyl, optionally substituted aryl or    optionally substituted aralkyl;-   or R⁴, together with the nitrogen to which it is attached, and a R²,    together with the adjacent carbon to which it is attached, together    form a fused 6-membered N-heterocyclyl of the following structure:

-   -   where        indicates the point of fusion and R^(4a), R^(4b), R^(4c), and        R^(4d) are each independently hydrogen, alkyl, halo or haloalkyl        or R^(4a) and R^(4b), together with the carbon to which they are        both attached, form a cycloalkyl or R^(4c) and R^(4d), together        with the carbon to which they are both attached, form a        cycloalkyl, and the remaining R², if present, is selected from        hydrogen, alkyl, halo or haloalkyl;

-   R⁵ is optionally substituted aryl or optionally substituted    N-heteroaryl; and

-   R⁶ is hydrogen, alkyl, haloalkyl, optionally substituted aryl or    optionally substituted aralkyl.

Of this embodiment, one embodiment is a compound selected from:

-   1-benzyl-N-(3-(morpholinomethyl)-1H-indol-5-yl)-1H-pyrazole-4-carboxamide    hydrochloride;-   1-benzyl-N-(3-(morpholinomethyl)-1H-indol-6-yl)-1H-pyrazole-4-carboxamide    hydrochloride;-   1-benzyl-N-(3-((4-methylpiperazin-1-yl)methyl)-1H-indol-5-yl)-1H-pyrazole-4-carboxamide    dihydrochloride;-   1-benzyl-N-(3-((4-methylpiperazin-1-yl)methyl)-1H-indol-6-yl)-1H-pyrazole-4-carboxamide    dihydrochloride;-   1-benzyl-N-(2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)-1H-pyrazole-4-carboxamide    hydrochloride;-   (S)-1-benzyl-N-(6-methyl-9-oxo-6,7,8,9-tetrahydropyrido[2′,3′:4,5]pyrrolo[1,2-a]pyrazin-3-yl)-1H-pyrazole-4-carboxamide;    and-   (S)-1-benzyl-N-(6-methyl-9-oxo-6,7,8,9-tetrahydropyrido[2′,3′:4,5]pyrrolo[1,2-a]pyrazin-2-yl)-1H-pyrazole-4-carboxamide.

Another embodiment of a compound of formula (Ia1) is a compound offormula (Ia1) wherein:

-   n is 1 or 2;-   B is —O—;-   E is —N═ or —C(R³)═;-   each R² is independently hydrogen, alkyl, halo, haloalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;-   or two R², together with the adjacent carbons to which they are    attached, form a fused optionally substituted 6-membered    N-heterocyclyl;-   each R³ is independently hydrogen, alkyl, haloalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl or optionally    substituted heteroarylalkyl;-   R⁵ is optionally substituted aryl or optionally substituted    N-heteroaryl; and-   R⁶ is hydrogen, alkyl, haloalkyl, optionally substituted aryl or    optionally substituted aralkyl.

Of this embodiment, an embodiment is a compound selected from:

-   1-benzyl-N-(3-(morpholinomethyl)benzofuran-6-yl)-1H-pyrazole-4-carboxamide    hydrochloride;-   1-benzyl-N-(3-(morpholinomethyl)benzofuran-5-yl)-1H-pyrazole-4-carboxamide    hydrochloride;-   1-benzyl-N-(3-(piperazin-1-ylmethyl)benzofuran-5-yl)-1H-pyrazole-4-carboxamide    dihydrochloride;-   1-benzyl-N-(3-(piperazin-1-ylmethyl)benzofuran-6-yl)-1H-pyrazole-4-carboxamide    dihydrochloride; and-   1-benzyl-N-(2-methyl-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridin-8-yl)-1H-pyrazole-4-carboxamide    hydrochloride.

Another embodiment of a compound of formula (Ia1) is a compound offormula (Ia1) wherein:

-   n is 1 or 2;-   B is —S(O)_(t) (where t is 0, 1 or 2)-;-   E is —N═ or —C(R³)═;-   each R² is independently hydrogen, alkyl, halo, haloalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;-   or two R², together with the adjacent carbons to which they are    attached, form a fused optionally substituted 6-membered    N-heterocyclyl;-   each R³ is independently hydrogen, alkyl, haloalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl or optionally    substituted heteroarylalkyl;-   R⁵ is optionally substituted aryl or optionally substituted    N-heteroaryl; and-   R⁶ is hydrogen, alkyl, haloalkyl, optionally substituted aryl or    optionally substituted aralkyl.

Of this embodiment, an embodiment is a compound selected from:

-   1-benzyl-N-(3-(morpholinomethyl)benzo[b]thiophen-5-yl)-1H-pyrazole-4-carboxamide    hydrochloride; and-   1-benzyl-N-(3-(piperazin-1-ylmethyl)benzo[b]thiophen-5-yl)-1H-pyrazole-4-carboxamide    dihydrochloride.

Of this embodiment, another embodiment is a compound of formula (Ia)wherein A is —N═, i.e., a compound having the formula (Ia2):

wherein:

-   n is 1 or 2;-   B is —O—, —N(R⁴)—, or —S(O)_(t) (where t is 0, 1 or 2)-;-   E is —N═ or —C(R³)═;-   each R² is independently hydrogen, alkyl, halo, haloalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;-   or two R², together with the adjacent carbons to which they are    attached, form a fused optionally substituted 6-membered    N-heterocyclyl;-   R³ is hydrogen, alkyl, haloalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heteroaryl or optionally substituted heteroarylalkyl;-   R⁴ is hydrogen, alkyl, haloalkyl, optionally substituted aryl or    optionally substituted aralkyl;-   or R⁴, together with the nitrogen to which it is attached, and a R²,    together with the adjacent carbon to which it is attached, together    form a fused 6-membered N-heterocyclyl of the following structure:

-   -   where        indicates the point of fusion and R^(4a), R^(4b), R^(4c), and        R^(4d) are each independently hydrogen, alkyl, halo or haloalkyl        or R^(4a) and R^(4b), together with the carbon to which they are        both attached, form a cycloalkyl or R^(4c) and R^(4d), together        with the carbon to which they are both attached, form a        cycloalkyl, and the remaining R², if present, is selected from        hydrogen, alkyl, halo or haloalkyl;

-   R⁵ is optionally substituted aryl or optionally substituted    N-heteroaryl; and

-   R⁶ is hydrogen, alkyl, haloalkyl, optionally substituted aryl or    optionally substituted aralkyl.

Of this embodiment, an embodiment is a compound of formula (Ia2)wherein:

-   n is 1 or 2;-   B is —N(R⁴)—;-   E is —N═ or —C(R³)═;-   each R² is independently hydrogen, alkyl, halo, haloalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;-   or two R², together with the adjacent carbons to which they are    attached, form a fused optionally substituted 6-membered    N-heterocyclyl;-   R³ is hydrogen, alkyl, haloalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heteroaryl or optionally substituted heteroarylalkyl;-   R⁴ is hydrogen, alkyl, haloalkyl, optionally substituted aryl or    optionally substituted aralkyl;-   or R⁴, together with the nitrogen to which it is attached, and a R²,    together with the adjacent carbon to which it is attached, together    form a fused 6-membered N-heterocyclyl of the following structure:

-   -   where        indicates the point of fusion and R^(4a), R^(4b), R^(4c) and        R^(4d) are each independently hydrogen, alkyl, halo or haloalkyl        or R^(4a) and R^(4b), together with the carbon to which they are        both attached, form a cycloalkyl or R^(4c) and R^(4d), together        with the carbon to which they are both attached, form a        cycloalkyl, and the remaining R², if present, is selected from        hydrogen, alkyl, halo or haloalkyl;

-   R⁵ is optionally substituted aryl or optionally substituted    N-heteroaryl; and

-   R⁶ is hydrogen, alkyl, haloalkyl, optionally substituted aryl or    optionally substituted aralkyl.

Of this embodiment, one embodiment is a compound selected from:

-   (R)-1-benzyl-N-(4-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indol-7-yl)-1H-pyrazole-4-carboxamide;-   1-benzyl-N-(1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indol-7-yl)-1H-pyrazole-4-carboxamide;-   1-benzyl-N-((9R)-9-methyl-6-oxo-5,5a,6,7,8,9-hexahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-2-yl)-1H-pyrazole-4-carboxamide;    and-   (R)-1-(3-aminobenzyl)-N-(9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-2-yl)-1H-pyrazole-4-carboxamide.

Another embodiment of a compound of formula (Ia2) is a compound offormula (Ia2) wherein:

-   n is 1 or 2;-   B is —O—;-   E is —N═ or —C(R³)═;-   each R² is independently hydrogen, alkyl, halo, haloalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;-   or two R², together with the adjacent carbons to which they are    attached, form a fused optionally substituted 6-membered    N-heterocyclyl;-   R³ is hydrogen, alkyl, haloalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heteroaryl or optionally substituted heteroarylalkyl;-   R⁵ is optionally substituted aryl or optionally substituted    N-heteroaryl; and-   R⁶ is hydrogen, alkyl, haloalkyl, optionally substituted aryl or    optionally substituted aralkyl.

Another embodiment of a compound of formula (Ia2) is a compound offormula (Ia2) wherein:

-   n is 1 or 2;-   B is —S(O)_(t) (where t is 0, 1 or 2)-;-   E is —N═ or —C(R³)═;-   each R² is independently hydrogen, alkyl, halo, haloalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;-   or two R², together with the adjacent carbons to which they are    attached, form a fused optionally substituted 6-membered    N-heterocyclyl;-   R³ is hydrogen, alkyl, haloalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heteroaryl or optionally substituted heteroarylalkyl;-   R⁵ is optionally substituted aryl or optionally substituted    N-heteroaryl; and-   R⁶ is hydrogen, alkyl, haloalkyl, optionally substituted aryl or    optionally substituted aralkyl.

Of the compounds of formula (I) as described above in the Summary of theInvention, one embodiment is the compounds of formula (I) wherein R¹ isR⁷—N(R⁶)C(O)—, i.e., a compound having the formula (Ib):

wherein:

-   n is 1 or 2;-   A is —N═ or —C(R³)═;-   B is —O—, —N(R⁴)—, or —S(O)_(t) (where t is 0, 1 or 2)-;-   E is —N═ or —C(R³)═;-   each R² is independently hydrogen, alkyl, halo, haloalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;-   or two R², together with the adjacent carbons to which they are    attached, form a fused optionally substituted 6-membered    N-heterocyclyl;-   each R³ is independently hydrogen, alkyl, haloalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl or optionally    substituted heteroarylalkyl;-   R⁴ is hydrogen, alkyl, haloalkyl, optionally substituted aryl or    optionally substituted aralkyl; or R⁴, together with the nitrogen to    which it is attached, and a R², together with the adjacent carbon to    which it is attached, together form a fused 6-membered    N-heterocyclyl of the following structure:

-   -   where        indicates the point of fusion and R^(4a), R^(4b), R^(4c), and        R^(4d) are each independently hydrogen, alkyl, halo or haloalkyl        or R^(4a) and R^(4b), together with the carbon to which they are        both attached, form a cycloalkyl or R^(4c) and R^(4d), together        with the carbon to which they are both attached, form a        cycloalkyl, and the remaining R², if present, is selected from        hydrogen, alkyl, halo or haloalkyl;

-   each R⁶ is independently hydrogen, alkyl, haloalkyl, optionally    substituted aryl or optionally substituted aralkyl; and

-   R⁷ is optionally substituted aryl or optionally substituted    N-heteroaryl when E is —N═; or R⁷ is a monocyclic N-heteroaryl    substituted with an optionally substituted aralkyl when E is —C(R³)═    and one R² is halo, haloalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heteroaryl or optionally substituted heteroarylalkyl;

-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and one of R^(4a) and R^(4b)    is not methyl and the other is not hydrogen;

-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and two of R^(4a), R^(4b),    R^(4c), and R^(4d) on adjacent carbons are not both methyl and the    other two are not both hydrogen;

-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and R^(4a) and R^(4b),    together with the carbon to which they are both attached, form a    cycloalkyl or R^(4c) and R^(4d), together with the carbon to which    they are both attached, form a cycloalkyl;

-   or R⁷ is a monocyclic N-heteroaryl substituted by an aralkyl    substituted with halo, haloalkyl, —CN, —NO₂, —N(R⁶)₂, —N(R⁶)C(O)OR⁶,    —C(O)R⁶, —C(O)OR⁶ or —C(O)N(R⁶)₂ when E is —C(R³)═ and R^(4a) is    methyl and R^(4b), R^(4c), and R^(4d) are each hydrogen or when E is    —C(R³)═ and R^(4a) and R^(4c) are each methyl and R^(4b) and R^(4d)    are each hydrogen;

-   or R⁷ is a monocyclic N-heteroaryl substituted with optionally    substituted N-heterocyclylalkyl when E is —C(R³)═.

Of this embodiment, an embodiment is a compound of formula (Ib) whereinA is —C(R³)═, i.e., a compound having the formula (Ib1):

wherein:

-   n is 1 or 2;-   B is —O—, —N(R⁴)—, or —S(O)_(t) (where t is 0, 1 or 2)-;-   E is —N═ or —C(R³)═;-   each R² is independently hydrogen, alkyl, halo, haloalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;-   or two R², together with the adjacent carbons to which they are    attached, form a fused optionally substituted 6-membered    N-heterocyclyl;-   each R³ is independently hydrogen, alkyl, haloalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl or optionally    substituted heteroarylalkyl;-   R⁴ is hydrogen, alkyl, haloalkyl, optionally substituted aryl or    optionally substituted aralkyl;-   or R⁴, together with the nitrogen to which it is attached, and a R²,    together with the adjacent carbon to which it is attached, together    form a fused 6-membered N-heterocyclyl of the following structure:

-   -   where        indicates the point of fusion and R^(4a), R^(4b), R^(4c), and        R^(4d) are each independently hydrogen, alkyl, halo or haloalkyl        or R^(4a) and R^(4b), together with the carbon to which they are        both attached, form a cycloalkyl or R^(4c) and R^(4d), together        with the carbon to which they are both attached, form a        cycloalkyl, and the remaining R², if present, is selected from        hydrogen, alkyl, halo or haloalkyl;

-   each R⁶ is independently hydrogen, alkyl, haloalkyl, optionally    substituted aryl or optionally substituted aralkyl; and

-   R⁷ is optionally substituted aryl or optionally substituted    N-heteroaryl when E is —N═;

-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and one R² is halo, haloalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;

-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and one of R^(4a) and R^(4b)    is not methyl and the other is not hydrogen;

-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and two of R^(4a), R^(4b),    R^(4c), and R^(4d) on adjacent carbons are not both methyl and the    other two are not both hydrogen;

-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and R^(4a) and R^(4b),    together with the carbon to which they are both attached, form a    cycloalkyl or R^(4c) and R^(4d), together with the carbon to which    they are both attached, form a cycloalkyl;

-   or R⁷ is a monocyclic N-heteroaryl substituted by an aralkyl    substituted with halo, haloalkyl, —CN, —NO₂, —N(R⁶)₂, —N(R⁶)C(O)OR⁶,    —C(O)R⁶, —C(O)OR⁶ or —C(O)N(R⁶)₂ when E is —C(R³)═ and R^(4a) is    methyl and R^(4b), R^(4c), and R^(4d) are each hydrogen or when E is    —C(R³)═ and R^(4a) and R^(4c) are each methyl and R^(4b) and R^(4d)    are each hydrogen;

-   or R⁷ is a monocyclic N-heteroaryl substituted with optionally    substituted N-heterocyclylalkyl when E is —C(R³)═.

Of this embodiment, an embodiment is a compound of formula (Ib1)wherein:

-   n is 1 or 2;-   B is —N(R⁴)—;-   E is —N═ or —C(R³)═;-   each R² is independently hydrogen, alkyl, halo, haloalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;-   or two R², together with the adjacent carbons to which they are    attached, form a fused optionally substituted 6-membered    N-heterocyclyl;-   each R³ is independently hydrogen, alkyl, haloalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl or optionally    substituted heteroarylalkyl;-   R⁴ is hydrogen, alkyl, haloalkyl, optionally substituted aryl or    optionally substituted aralkyl;-   R⁴ is hydrogen, alkyl, haloalkyl, optionally substituted aryl or    optionally substituted aralkyl;-   or R⁴, together with the nitrogen to which it is attached, and a R²,    together with the adjacent carbon to which it is attached, together    form a fused 6-membered N-heterocyclyl of the following structure:

-   -   where        indicates the point of fusion and R^(4a), R^(4b), R^(4c), and        R^(4d) are each independently hydrogen, alkyl, halo or haloalkyl        or R^(4a) and R^(4b), together with the carbon to which they are        both attached, form a cycloalkyl or R^(4c) and R^(4d), together        with the carbon to which they are both attached, form a        cycloalkyl, and the remaining R², if present, is selected from        hydrogen, alkyl, halo or haloalkyl;

-   R⁷ is optionally substituted aryl or optionally substituted    N-heteroaryl when E is —N═;

-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and one R² is halo, haloalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;

-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and one of R^(4a) and R^(4b)    is not methyl and the other is not hydrogen;

-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and two of R^(4a), R^(4b),    R^(4c), and R^(4d) on adjacent carbons are not both methyl and the    other two are not both hydrogen;

-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and R^(4a) and R^(4b),    together with the carbon to which they are both attached, form a    cycloalkyl or R^(4c) and R^(4d), together with the carbon to which    they are both attached, form a cycloalkyl;

-   or R⁷ is a monocyclic N-heteroaryl substituted by an aralkyl    substituted with halo, haloalkyl, —CN, —NO₂, —N(R⁶)₂, —N(R⁶)C(O)OR⁶,    —C(O)R⁶, —C(O)OR⁶ or —C(O)N(R⁶)₂ when E is —C(R³)═ and R^(4a) is    methyl and R^(4b), R^(4c), and R^(4d) are each hydrogen or when E is    —C(R³)═ and R^(4a) and R^(4c) are each methyl and R^(4b) and R^(4d)    are each hydrogen;

-   or R⁷ is a monocyclic N-heteroaryl substituted with optionally    substituted N-heterocyclylalkyl when E is —C(R³)═.

Of this embodiment, one embodiment is a compound selected from:

-   (S)—N-(1-benzyl-1H-pyrazol-4-yl)-6-methyl-9-oxo-6,7,8,9-tetrahydropyrido[2′,3′:4,5]pyrrolo[1,2-a]pyrazine-3-carboxamide;    and-   (S)—N-(1-benzyl-1H-pyrazol-4-yl)-6-methyl-9-oxo-6,7,8,9-tetrahydropyrido[2′,3′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide.

Another embodiment of a compound of formula (Ib1) is a compound offormula (Ib1) wherein:

-   n is 1 or 2;-   B is —O—;-   E is —N═ or —C(R³)═;-   each R² is independently hydrogen, alkyl, halo, haloalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;-   or two R², together with the adjacent carbons to which they are    attached, form a fused optionally substituted 6-membered    N-heterocyclyl;-   each R³ is independently hydrogen, alkyl, haloalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl or optionally    substituted heteroarylalkyl;-   each R⁶ is independently hydrogen, alkyl, haloalkyl, optionally    substituted aryl or optionally substituted aralkyl; and-   R⁷ is optionally substituted aryl or optionally substituted    N-heteroaryl when E is —N═;-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and one R² is halo, haloalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and one of R^(4a) and R^(4b)    is not methyl and the other is not hydrogen;-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and two of R^(4a), R^(4b),    R^(4c), and R^(4d) on adjacent carbons are not both methyl and the    other two are not both hydrogen;-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and R^(4a) and R^(4b),    together with the carbon to which they are both attached, form a    cycloalkyl or R^(4c) and R^(4d), together with the carbon to which    they are both attached, form a cycloalkyl;-   or R⁷ is a monocyclic N-heteroaryl substituted by an aralkyl    substituted with halo, haloalkyl, —CN, —NO₂, —N(R⁶)₂, —N(R⁶)C(O)OR⁶,    —C(O)R⁶, —C(O)OR⁶ or —C(O)N(R⁶)₂ when E is —C(R³)═ and R^(4a) is    methyl and R^(4b), R^(4c), and R^(4d) are each hydrogen or when E is    —C(R³)═ and R^(4a) and R^(4C) are each methyl and R^(4b) and R^(4d)    are each hydrogen;-   or R⁷ is a monocyclic N-heteroaryl substituted with optionally    substituted N-heterocyclylalkyl when E is —C(R³)═.

Another embodiment of a compound of formula (Ib1) is a compound offormula (Ib1) wherein:

-   n is 1 or 2;-   B is —S(O)_(t) (where t is 0, 1 or 2)-;-   E is —N═ or —C(R³)═;-   each R² is independently hydrogen, alkyl, halo, haloalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;-   or two R², together with the adjacent carbons to which they are    attached, form a fused optionally substituted 6-membered    N-heterocyclyl;-   each R³ is independently hydrogen, alkyl, haloalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl or optionally    substituted heteroarylalkyl;-   each R⁶ is independently hydrogen, alkyl, haloalkyl, optionally    substituted aryl or optionally substituted aralkyl; and-   R⁷ is optionally substituted aryl or optionally substituted    N-heteroaryl when E is —N═;-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and one R² is halo, haloalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and one of R^(4a) and R^(4b)    is not methyl and the other is not hydrogen;-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and two of R^(4a), R^(4b),    R^(4c), and R^(4d) on adjacent carbons are not both methyl and the    other two are not both hydrogen;-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and R^(4a) and R^(4b),    together with the carbon to which they are both attached, form a    cycloalkyl or R^(4c) and R^(4d), together with the carbon to which    they are both attached, form a cycloalkyl;-   or R⁷ is a monocyclic N-heteroaryl substituted by an aralkyl    substituted with halo, haloalkyl, —CN, —NO₂, —N(R⁶)₂, —N(R⁶)C(O)OR⁶,    —C(O)R⁶, —C(O)OR⁶ or —C(O)N(R⁶)₂ when E is —C(R³)═ and R^(4a) is    methyl and R^(4b), R^(4c), and R^(4d) are each hydrogen or when E is    —C(R³)═ and R^(4a) and R^(4c) are each methyl and R^(4b) and R^(4d)    are each hydrogen;-   or R⁷ is a monocyclic N-heteroaryl substituted with optionally    substituted N-heterocyclylalkyl when E is —C(R³)═.

Of this embodiment, another embodiment is a compound of formula (Ib)wherein A is —N═, i.e., a compound having the formula (Ib2):

wherein:

-   n is 1 or 2;-   B is —O—, —N(R⁴)—, or —S(O)_(t) (where t is 0, 1 or 2)-;-   E is —N═ or —C(R³)═;-   each R² is independently hydrogen, alkyl, halo, haloalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;-   or two R², together with the adjacent carbons to which they are    attached, form a fused optionally substituted 6-membered    N-heterocyclyl;-   R³ is hydrogen, alkyl, haloalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heteroaryl or optionally substituted heteroarylalkyl;-   R⁴ is hydrogen, alkyl, haloalkyl, optionally substituted aryl or    optionally substituted aralkyl;-   or R⁴, together with the nitrogen to which it is attached, and a R²,    together with the adjacent carbon to which it is attached, together    form a fused 6-membered N-heterocyclyl of the following structure:

-   -   where        indicates the point of fusion and R^(4a), R^(4b), R^(4c), and        R^(4d) are each independently hydrogen, alkyl, halo or haloalkyl        or R^(4a) and R^(4b), together with the carbon to which they are        both attached, form a cycloalkyl or R^(4c) and R^(4d), together        with the carbon to which they are both attached, form a        cycloalkyl, and the remaining R², if present, is selected from        hydrogen, alkyl, halo or haloalkyl;

-   each R⁶ is independently hydrogen, alkyl, haloalkyl, optionally    substituted aryl or optionally substituted aralkyl;

-   R⁷ is optionally substituted aryl or optionally substituted    N-heteroaryl when E is —N═;

-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and one R² is halo, haloalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;

-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and one of R^(4a) and R^(4b)    is not methyl and the other is not hydrogen;

-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and two of R^(4a), R^(4b),    R^(4c), and R^(4d) on adjacent carbons are not both methyl and the    other two are not both hydrogen;

-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and R^(4a) and R^(4b),    together with the carbon to which they are both attached, form a    cycloalkyl or R^(4c) and R^(4d), together with the carbon to which    they are both attached, form a cycloalkyl;

-   or R⁷ is a monocyclic N-heteroaryl substituted by an aralkyl    substituted with halo, haloalkyl, —CN, —NO₂, —N(R⁶)₂, —N(R⁶)C(O)OR⁶,    —C(O)R⁶, —C(O)OR⁶ or —C(O)N(R⁶)₂ when E is —C(R³)═ and R^(4a) is    methyl and R^(4b), R^(4c), and R^(4d) are each hydrogen or when E is    —C(R³)═ and R^(4a) and R^(4c) are each methyl and R^(4b) and R^(4d)    are each hydrogen;

-   or R⁷ is a monocyclic N-heteroaryl substituted with optionally    substituted N-heterocyclylalkyl when E is —C(R³)═.

Of this embodiment, an embodiment is a compound of formula (Ib2)wherein:

-   n is 1 or 2;-   B is —N(R⁴)—;-   E is —N═ or —C(R³)═;-   each R² is independently hydrogen, alkyl, halo, haloalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;-   or two R², together with the adjacent carbons to which they are    attached, form a fused optionally substituted 6-membered    N-heterocyclyl;-   R³ is hydrogen, alkyl, haloalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heteroaryl or optionally substituted heteroarylalkyl;-   R⁴ is hydrogen, alkyl, haloalkyl, optionally substituted aryl or    optionally substituted aralkyl;-   or R⁴, together with the nitrogen to which it is attached, and a R²,    together with the adjacent carbon to which it is attached, together    form a fused 6-membered N-heterocyclyl of the following structure:

-   -   where        indicates the point of fusion and R^(4a), R^(4b), R^(4c), and        R^(4d) are each independently hydrogen, alkyl, halo or haloalkyl        or R^(4a) and R^(4b), together with the carbon to which they are        both attached, form a cycloalkyl or R^(4c) and R^(4d), together        with the carbon to which they are both attached, form a        cycloalkyl, and the remaining R², if present, is selected from        hydrogen, alkyl, halo or haloalkyl;

-   each R⁶ is independently hydrogen, alkyl, haloalkyl, optionally    substituted aryl or optionally substituted aralkyl; and

-   R⁷ is optionally substituted aryl or optionally substituted    N-heteroaryl when E is —N═;

-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and one R² is halo, haloalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;

-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and one of R^(4a) and R^(4b)    is not methyl and the other is not hydrogen;

-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and two of R^(4a), R^(4b),    R^(4c), and R^(4d) on adjacent carbons are not both methyl and the    other two are not both hydrogen;

-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and R^(4a) and R^(4b),    together with the carbon to which they are both attached, form a    cycloalkyl or R^(4c) and R^(4d), together with the carbon to which    they are both attached, form a cycloalkyl;

-   or R⁷ is a monocyclic N-heteroaryl substituted by an aralkyl    substituted with halo, haloalkyl, —CN, —NO₂, —N(R⁶)₂, —N(R⁶)C(O)OR⁶,    —C(O)R⁶, —C(O)OR⁶ or —C(O)N(R⁶)₂ when E is —C(R³)═ and R^(4a) is    methyl and R^(4b), R^(4c), and R^(4d) are each hydrogen or when E is    —C(R³)═ and R^(4a) and R^(4c) are each methyl and R^(4b) and R^(4d)    are each hydrogen;

-   or R⁷ is a monocyclic N-heteroaryl substituted with optionally    substituted N-heterocyclylalkyl when E is —C(R³)═.

Of this embodiment, one embodiment is a compound selected from:

-   (R)—N-(1-(3-aminobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;-   (R)—N-(1-(2-aminobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;-   (R)—N-(1-(4-aminobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;-   (R)—N-(1-benzyl-1H-pyrazol-4-yl)-5-fluoro-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;-   (R)—N-(1-benzyl-1H-pyrazol-4-yl)-9-isopropyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;-   (S)—N-(1-benzyl-1H-pyrazol-4-yl)-9-trifluoromethyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;-   N-(1-benzyl-1H-pyrazol-4-yl)-6′-oxo-7′,8′-dihydro-6′H-spiro[cyclopropane-1,9′-pyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine]-2′-carboxamide;-   (R)—N-(1-(4-methylpiperazinyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;-   (R)—N-(1-benzyl-1H-pyrazol-4-yl)-5-chloro-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;-   (S)—N-(1-benzyl-1H-pyrazol-4-yl)-9-isopropyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;-   (R)—N-(1-benzyl-1H-pyrazol-4-yl)-9-trifluoromethyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;-   N-(1-benzyl-1H-pyrazol-4-yl)-9,9-dimethyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;-   (R)-5-fluoro-9-methyl-N-(1-((4-methylpiperazin-1-yl)methyl)-1H-pyrazol-4-yl)-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;-   (R)-5-fluoro-9-methyl-N-(1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;    and-   (R)—N-(1-benzyl-1H-pyrazol-4-yl)-6-methyl-9-oxo-6,7,8,9-tetrahydropyrrolo[1,5-a:2,3-b′]dipyrazine-3-carboxamide.

Another embodiment of a compound of formula (Ib2) is a compound offormula (Ib2) wherein:

-   n is 1 or 2;-   B is —O—;-   E is —N═ or —C(R³)═;-   each R² is independently hydrogen, alkyl, halo, haloalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;-   or two R², together with the adjacent carbons to which they are    attached, form a fused optionally substituted 6-membered    N-heterocyclyl;-   R³ is hydrogen, alkyl, haloalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heteroaryl or optionally substituted heteroarylalkyl;-   each R⁶ is independently hydrogen, alkyl, haloalkyl, optionally    substituted aryl or optionally substituted aralkyl; and-   R⁷ is optionally substituted aryl or optionally substituted    N-heteroaryl when E is —N═;-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and one R² is halo, haloalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and one of R^(4a) and R^(4b)    is not methyl and the other is not hydrogen;-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and two of R^(4a), R^(4b),    R^(4c), and R^(4d) on adjacent carbons are not both methyl and the    other two are not both hydrogen;-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and R^(4a) and R^(4b),    together with the carbon to which they are both attached, form a    cycloalkyl or R^(4c) and R^(4d), together with the carbon to which    they are both attached, form a cycloalkyl;-   or R⁷ is a monocyclic N-heteroaryl substituted by an aralkyl    substituted with halo, haloalkyl, —CN, —NO₂, —N(R⁶)₂, —N(R⁶)C(O)OR⁶,    —C(O)R⁶, —C(O)OR⁶ or —C(O)N(R⁶)₂ when E is —C(R³)═ and R^(4a) is    methyl and R^(4b), R^(4c), and R^(4d) are each hydrogen or when E is    —C(R³)═ and R^(4a) and R^(4C) are each methyl and R^(4b) and R^(4d)    are each hydrogen;-   or R⁷ is a monocyclic N-heteroaryl substituted with optionally    substituted N-heterocyclylalkyl when E is —C(R³)═.

Another embodiment of a compound of formula (Ib2) is a compound offormula (Ib2) wherein:

-   n is 1 or 2;-   B is —S(O)_(t) (where t is 0, 1 or 2)-;-   E is —N═ or —C(R³)═;-   each R² is independently hydrogen, alkyl, halo, haloalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;-   or two R², together with the adjacent carbons to which they are    attached, form a fused optionally substituted 6-membered    N-heterocyclyl;-   R³ is hydrogen, alkyl, haloalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heteroaryl or optionally substituted heteroarylalkyl;-   each R⁶ is independently hydrogen, alkyl, haloalkyl, optionally    substituted aryl or optionally substituted aralkyl; and-   R⁷ is optionally substituted aryl or optionally substituted    N-heteroaryl when E is —N═;-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and one R² is halo, haloalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and one of R^(4a) and R^(4b)    is not methyl and the other is not hydrogen;-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and two of R^(4a), R^(4b),    R^(4c), and R^(4d) on adjacent carbons are not both methyl and the    other two are not both hydrogen;-   or R⁷ is a monocyclic N-heteroaryl substituted with an optionally    substituted aralkyl when E is —C(R³)═ and R^(4a) and R^(4b),    together with the carbon to which they are both attached, form a    cycloalkyl or R^(4c) and R^(4d), together with the carbon to which    they are both attached, form a cycloalkyl;-   or R⁷ is a monocyclic N-heteroaryl substituted by an aralkyl    substituted with halo, haloalkyl, —CN, —NO₂, —N(R⁶)₂, —N(R⁶)C(O)OR⁶,    —C(O)R⁶, —C(O)OR⁶ or —C(O)N(R⁶)₂ when E is —C(R³)═ and R^(4a) is    methyl and R^(4b), R^(4c), and R^(4d) are each hydrogen or when E is    —C(R³)═ and R^(4a) and R^(4c) are each methyl and R^(4b) and R^(4d)    are each hydrogen;-   or R⁷ is a monocyclic N-heteroaryl substituted with optionally    substituted N-heterocyclylalkyl when E is —C(R³)═.

Of the compounds of formula (I) as described above in the Summary of theInvention, one embodiment is the compounds of formula (I) wherein R¹ isR⁵—N(R⁶)C(O)N(R⁶)—, i.e., a compound having the formula (Ic):

wherein:

-   n is 1 or 2;-   A is —N═ or —C(R³)═;-   B is —O—, —N(R⁴)—, or —S(O)_(t) (where t is 0, 1 or 2)-;-   E is —N═ or —C(R³)═;-   each R² is independently hydrogen, alkyl, halo, haloalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;-   or two R², together with the adjacent carbons to which they are    attached, form a fused optionally substituted 6-membered    N-heterocyclyl;-   each R³ is independently hydrogen, alkyl, haloalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl or optionally    substituted heteroarylalkyl;-   R⁴ is hydrogen, alkyl, haloalkyl, optionally substituted aryl or    optionally substituted aralkyl;-   or R⁴, together with the nitrogen to which it is attached, and a R²,    together with the adjacent carbon to which it is attached, together    form a fused 6-membered N-heterocyclyl of the following structure:

-   -   where        indicates the point of fusion and R^(4a), R^(4b), R^(4c), and        R^(4d) are each independently hydrogen, alkyl, halo or haloalkyl        or R^(4a) and R^(4b), together with the carbon to which they are        both attached, form a cycloalkyl or R^(4c) and R^(4d), together        with the carbon to which they are both attached, form a        cycloalkyl, and the remaining R², if present, is selected from        hydrogen, alkyl, halo or haloalkyl;

-   R⁵ is optionally substituted aryl or optionally substituted    N-heteroaryl; and

-   each R⁶ is independently hydrogen, alkyl, haloalkyl, optionally    substituted aryl or optionally substituted aralkyl.

Of this embodiment, one embodiment is a compound which is(R)-1-(1-benzyl-1H-pyrazol-4-yl)-3-(9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-2-yl)urea.

Of the compounds of formula (I) as described above in the Summary of theInvention, one embodiment is the compounds of formula (I) wherein R¹ isR¹ is R⁵—N(R⁶)C(═NR⁶)N(R⁶)—, i.e., a compound having the formula (Id):

wherein:

-   n is 1 or 2;-   A is —N═ or —C(R³)═;-   B is —O—, —N(R⁴)—, or —S(O)_(t) (where t is 0, 1 or 2)-;-   E is —N═ or —C(R³)═;-   each R² is independently hydrogen, alkyl, halo, haloalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl or    optionally substituted heteroarylalkyl;-   or two R², together with the adjacent carbons to which they are    attached, form a fused optionally substituted 6-membered    N-heterocyclyl;-   each R³ is independently hydrogen, alkyl, haloalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heteroaryl or optionally    substituted heteroarylalkyl;-   R⁴ is hydrogen, alkyl, haloalkyl, optionally substituted aryl or    optionally substituted aralkyl;-   or R⁴, together with the nitrogen to which it is attached, and a R²,    together with the adjacent carbon to which it is attached, together    form a fused 6-membered N-heterocyclyl of the following structure:

-   -   where        indicates the point of fusion and R^(4a), R^(4b), R^(4c), and        R^(4d) are each independently hydrogen, alkyl, halo or haloalkyl        or R^(4a) and R^(4b), together with the carbon to which they are        both attached, form a cycloalkyl or R^(4c) and R^(4d), together        with the carbon to which they are both attached, form a        cycloalkyl, and the remaining R², if present, is selected from        hydrogen, alkyl, halo or haloalkyl;

-   R⁵ is optionally substituted aryl or optionally substituted    N-heteroaryl; and

-   each R⁶ is independently hydrogen, alkyl, haloalkyl, optionally    substituted aryl or optionally substituted aralkyl.    Of this embodiment, one embodiment is a compound which is    (R)-1-(1-benzyl-1H-pyrazol-4-yl)-3-(9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-2-yl)guanidine.

In another aspect is a compound of formula (II) having the structure:

wherein:

-   R² is independently hydrogen, halo, C₁₋₆alkyl, or C₁₋₆haloalkyl;-   R^(4a) and R^(4b) are each independently hydrogen, halo, C₁₋₆alkyl,    or C₁₋₆haloalkyl; or R^(4a) and R^(4b), together with the carbon to    which they are both attached, form a cycloalkyl;-   each R⁶ is independently hydrogen or C₁₋₆alkyl;-   R¹¹ is halo, C₁₋₆haloalkyl, —N(R⁶)₂, —C₁₋₆alkyl-N(R⁶)₂, or    —C(O)N(R⁶)₂;-   each R¹² is independently —OH, —CN, halo, C₁₋₆alkyl, C₁₋₆haloalkyl,    C₁₋₆alkoxy, C₁₋₆haloalkoxy, —N(R⁶)₂, —C₁₋₆alkyl-N(R⁶)₂, —C(O)R⁶,    —C(O)OR⁶, —C(O)N(R⁶)₂, aryl, aralkyl, cycloalkyl, heterocyclyl, or    heteroaryl; and-   n is 0, 1, 2, 3, or 4;-   as an individual stereoisomer, enantiomer or tautomer thereof or a    mixture thereof;-   or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In some embodiments is a compound of formula (II) wherein R² ishydrogen. In some embodiments is a compound of formula (II) wherein R²is halo. In some embodiments is a compound of formula (II) wherein R² is—F. In some embodiments is a compound of formula (II) wherein R² is —Cl.In some embodiments is a compound of formula (II) wherein R² is C₁₋₆alkyl. In some embodiments is a compound of formula (II) wherein R² is—CH₃. In some embodiments is a compound of formula (II) wherein R² is—CH₂CH₃. In some embodiments is a compound of formula (II) wherein R² is—CH(CH₃)₂. In some embodiments is a compound of formula (II) wherein R²is C₁₋₆haloalkyl. In some embodiments is a compound of formula (II)wherein R² is —CF₃.

In some embodiments is a compound of formula (II) wherein R^(4a) ishydrogen. In some embodiments is a compound of formula (II) whereinR^(4a) is halo. In some embodiments is a compound of formula (II)wherein R^(4a) is —F. In some embodiments is a compound of formula (II)wherein R^(4a) is —Cl. In some embodiments is a compound of formula (II)wherein R^(4a) is C₁₋₆ alkyl. In some embodiments is a compound offormula (II) wherein R^(4a) is —CH₃. In some embodiments is a compoundof formula (II) wherein R^(4a) is —CH₂CH₃. In some embodiments is acompound of formula (II) wherein R^(4a) is —CH(CH₃)₂. In someembodiments is a compound of formula (II) wherein R^(4b) is hydrogen. Insome embodiments is a compound of formula (II) wherein R^(4b) is halo.In some embodiments is a compound of formula (II) wherein R^(4b) is —F.In some embodiments is a compound of formula (II) wherein R^(4b) is —Cl.In some embodiments is a compound of formula (II) wherein R^(4b) isC₁₋₆alkyl. In some embodiments is a compound of formula (II) whereinR^(4b) is —CH₃. In some embodiments is a compound of formula (II)wherein R^(4b) is —CH₂CH₃. In some embodiments is a compound of formula(II) wherein R^(4b) is —CH(CH₃)₂. In some embodiments is a compound offormula (II) wherein R^(4b) is C₁₋₆haloalkyl. In some embodiments is acompound of formula (II) wherein R^(4b) is —CF₃. In some embodiments isa compound of formula (II) wherein R^(4a) is C₁₋₆alkyl and R^(4b) ishydrogen. In some embodiments is a compound of formula (II) whereinR^(4a) is —CH₃ and R^(4b) is hydrogen. In some embodiments is a compoundof formula (II) wherein R^(4a) and R^(4b), together with the carbon towhich they are both attached, form a cycloalkyl. In some embodiments isa compound of formula (II) wherein R^(4a) and R^(4b), together with thecarbon to which they are both attached, form a cyclopropyl. In someembodiments is a compound of formula (II) wherein R^(4a) and R^(4b)together with the carbon to which they are both attached, form acyclobutyl. In some embodiments is a compound of formula (II) whereinR^(4a) and R^(4b), together with the carbon to which they are bothattached, form a cyclopentyl. In some embodiments is a compound offormula (II) wherein R^(4a) and R^(4b), together with the carbon towhich they are both attached, form a cyclohexyl.

In some embodiments is a compound of formula (II) wherein each R¹² isindependently —OH, —CN, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy, —N(R⁶)₂, —C₁₋₆alkyl-N(R⁶)₂, —C(O)R⁶, —C(O)OR⁶, or—C(O)N(R⁶)₂. In some embodiments is a compound of formula (II) whereineach R¹² is independently halo, C₁₋₆alkyl, —N(R⁶)₂, —C₁₋₆alkyl-N(R⁶)₂,or C₁₋₆haloalkyl. In some embodiments is a compound of formula (II)wherein R¹² is halo. In some embodiments is a compound of formula (II)wherein R¹² is —F. In some embodiments is a compound of formula (II)wherein R¹² is —Cl. In some embodiments is a compound of formula (II)wherein R¹² is C₁₋₆haloalkyl. In some embodiments is a compound offormula (II) wherein R¹² is —CF₃. In some embodiments is a compound offormula (II) wherein R¹² is —N(R⁶)₂. In some embodiments is a compoundof formula (II) wherein R¹² is —NH₂. In some embodiments is a compoundof formula (II) wherein R¹² is —C₁₋₆alkyl-N(R⁶)₂. In some embodiments isa compound of formula (II) wherein R¹² is —CH₂N(R⁶)₂. In someembodiments is a compound of formula (II) wherein R¹² is —CH₂NH₂. Insome embodiments is a compound of formula (II) wherein R¹² is—C(O)N(R⁶)₂. In some embodiments is a compound of formula (II) whereinR¹² is —C(O)NH₂. In some embodiments is a compound of formula (II)wherein n is 3. In some embodiments is a compound of formula (II)wherein n is 2. In some embodiments is a compound of formula (II)wherein n is 1. In some embodiments is a compound of formula (II)wherein n is 0. In some embodiments is a compound of formula (II)wherein n is 1 and R¹² is halo. In some embodiments is a compound offormula (II) wherein n is 1 and R¹² is —F. In some embodiments is acompound of formula (II) wherein n is 1 and R¹² is —Cl. In someembodiments is a compound of formula (II) wherein n is 1 and R¹² isC₁₋₆haloalkyl. In some embodiments is a compound of formula (II) whereinn is 1 and R¹² is —CF₃. In some embodiments is a compound of formula(II) wherein n is 1 and R¹² is —N(R⁶)₂. In some embodiments is acompound of formula (II) wherein n is 1 and R¹² is —NH₂. In someembodiments is a compound of formula (II) wherein n is 1 and R¹² is—C₁₋₆alkyl-N(R⁶)₂. In some embodiments is a compound of formula (II)wherein n is 1 and R¹² is —CH₂N(R⁶)₂. In some embodiments is a compoundof formula (II) wherein n is 1 and R¹² is —CH₂NH₂. In some embodimentsis a compound of formula (II) wherein n is 1 and R¹² is —C(O)N(R⁶)₂. Insome embodiments is a compound of formula (II) wherein n is 1 and R¹² is—C(O)NH₂.

In some embodiments is a compound of formula (II) wherein R¹¹ is halo.In some embodiments is a compound of formula (II) wherein R¹¹ is —F. Insome embodiments is a compound of formula (II) wherein R¹¹ is —Cl. Insome embodiments is a compound of formula (II) wherein R¹¹ isC₁₋₆haloalkyl. In some embodiments is a compound of formula (II) whereinR¹¹ is —CF₃. In some embodiments is a compound of formula (II) whereinR¹ is —N(R⁶)₂. In some embodiments is a compound of formula (II) whereinR¹¹ is —NH₂. In some embodiments is a compound of formula (II) whereinR¹¹ is —N(H)CH₃. In some embodiments is a compound of formula (II)wherein R¹¹ is —N(CH₃)₂. In some embodiments is a compound of formula(II) wherein R¹¹ is —C₁₋₆alkyl-N(R⁶)₂. In some embodiments is a compoundof formula (II) wherein R¹¹ is —CH₂N(R⁶)₂. In some embodiments is acompound of formula (II) wherein R¹¹ is —CH₂NH₂. In some embodiments isa compound of formula (II) wherein R¹¹ is —CH₂N(H)CH₃. In someembodiments is a compound of formula (II) wherein R¹¹ is —CH₂N(CH₃)₂. Insome embodiments is a compound of formula (II) wherein R¹¹ is—CH₂CH₂N(R⁶)₂. In some embodiments is a compound of formula (II) whereinR¹¹ is —CH₂CH₂NH₂. In some embodiments is a compound of formula (II)wherein R¹¹ is —CH₂CH₂N(H)CH₃. In some embodiments is a compound offormula (II) wherein R¹¹ is —CH₂CH₂N(CH₃)₂. In some embodiments is acompound of formula (II) wherein R¹¹ is —CH₂CH₂CH₂N(R⁶)₂. In someembodiments is a compound of formula (II) wherein R¹¹ is —CH₂CH₂CH₂NH₂.In some embodiments is a compound of formula (II) wherein R¹¹ is—CH₂CH₂CH₂N(H)CH₃. In some embodiments is a compound of formula (II)wherein R¹¹ is —CH₂CH₂CH₂N(CH₃)₂. In some embodiments is a compound offormula (II) wherein R¹¹ is —N(R⁶)₂ or —C₁₋₆alkyl-N(R⁶)₂. In someembodiments is a compound of formula (II) wherein R¹¹ is —C(O)N(R⁶)₂. Insome embodiments is a compound of formula (II) wherein R¹¹ is —C(O)NH₂.In some embodiments is a compound of formula (II) wherein R¹ is—C(O)N(H)CH₃. In some embodiments is a compound of formula (II) whereinR¹¹ is —C(O)N(CH₃)₂.

In another aspect is a compound of formula (III) having the structure:

wherein:

-   R² is independently halo, C₁₋₆alkyl, or C₁₋₆haloalkyl;-   R^(4a) and R^(4b) are each independently hydrogen, halo, C₁₋₆alkyl,    or C₁₋₆haloalkyl; or R^(4a) and R^(4b) together with the carbon to    which they are both attached, form a cycloalkyl;-   each R⁶ is independently hydrogen or C₁₋₆alkyl;-   each R¹² is independently —OH, —CN, halo, C₁₋₆alkyl, C₁₋₆haloalkyl,    C₁₋₆alkoxy, C₁₋₆haloalkoxy, —N(R⁶)₂, —C₁₋₆alkyl-N(R⁶)₂, —C(O)R⁶,    —C(O)OR⁶, —C(O)N(R⁶)₂, aryl, aralkyl, cycloalkyl, heterocyclyl, or    heteroaryl; and-   n is 0, 1, 2, 3, or 4;-   as an individual stereoisomer, enantiomer or tautomer thereof or a    mixture thereof;-   or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In some embodiments is a compound of formula (III) wherein R² is halo.In some embodiments is a compound of formula (III) wherein R² is —F. Insome embodiments is a compound of formula (III) wherein R² is —Cl. Insome embodiments is a compound of formula (III) wherein R² is C₁₋₆alkyl.In some embodiments is a compound of formula (III) wherein R² is —CH₃.In some embodiments is a compound of formula (III) wherein R² is—CH₂CH₃. In some embodiments is a compound of formula (III) wherein R²is —CH(CH₃)₂. In some embodiments is a compound of formula (III) whereinR² is C₁₋₆haloalkyl. In some embodiments is a compound of formula (III)wherein R² is —CF₃.

In some embodiments is a compound of formula (III) wherein R^(4a) ishydrogen. In some embodiments is a compound of formula (III) whereinR^(4a) is halo. In some embodiments is a compound of formula (III)wherein R^(4a) is —F. In some embodiments is a compound of formula (III)wherein R^(4a) is —Cl. In some embodiments is a compound of formula(III) wherein R^(4a) is C₁₋₆ alkyl. In some embodiments is a compound offormula (III) wherein R^(4a) is —CH₃. In some embodiments is a compoundof formula (III) wherein R^(4a) is —CH₂CH₃. In some embodiments is acompound of formula (III) wherein R^(4a) is —CH(CH₃)₂. In someembodiments is a compound of formula (III) wherein R^(4b) is hydrogen.In some embodiments is a compound of formula (III) wherein R^(4b) ishalo. In some embodiments is a compound of formula (III) wherein R^(4b)is —F. In some embodiments is a compound of formula (III) wherein R^(4b)is —Cl. In some embodiments is a compound of formula (III) whereinR^(4b) is C₁₋₆alkyl. In some embodiments is a compound of formula (III)wherein R^(4b) is —CH₃. In some embodiments is a compound of formula(III) wherein R^(4b) is —CH₂CH₃. In some embodiments is a compound offormula (III) wherein R^(4b) is —CH(CH₃)₂. In some embodiments is acompound of formula (III) wherein R^(4b) is C₁₋₆haloalkyl. In someembodiments is a compound of formula (III) wherein R^(4b) is —CF₃. Insome embodiments is a compound of formula (III) wherein R^(4a) isC₁₋₆alkyl and R^(4b) is hydrogen. In some embodiments is a compound offormula (III) wherein R^(4a) is —CH₃ and R^(4b) is hydrogen. In someembodiments is a compound of formula (III) wherein R^(4a) and R^(4b),together with the carbon to which they are both attached, form acycloalkyl. In some embodiments is a compound of formula (III) whereinR^(4a) and R^(4b), together with the carbon to which they are bothattached, form a cyclopropyl. In some embodiments is a compound offormula (III) wherein R^(4a) and R^(4b), together with the carbon towhich they are both attached, form a cyclobutyl. In some embodiments isa compound of formula (III) wherein R^(4a) and R^(4b), together with thecarbon to which they are both attached, form a cyclopentyl. In someembodiments is a compound of formula (III) wherein R^(4a) and R^(4b),together with the carbon to which they are both attached, form acyclohexyl.

In some embodiments is a compound of formula (III) wherein each R¹² isindependently —OH, —CN, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy, —N(R⁶)₂, —C₁₋₆alkyl-N(R⁶)₂, —C(O)R⁶, —C(O)OR⁶, or—C(O)N(R⁶)₂. In some embodiments is a compound of formula (III) whereineach R¹² is independently halo, C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁶)₂,—C₁₋₆alkyl-N(R⁶)₂, or —C(O)N(R⁶)₂. In some embodiments is a compound offormula (III) wherein each R¹² is independently halo, C₁₋₆alkyl,—N(R⁶)₂, —C₁₋₆alkyl-N(R⁶)₂, or C₁₋₆haloalkyl. In some embodiments is acompound of formula (III) wherein R¹² is halo. In some embodiments is acompound of formula (III) wherein R¹² is —F. In some embodiments is acompound of formula (III) wherein R¹² is —Cl. In some embodiments is acompound of formula (III) wherein R¹² is C₁₋₆ haloalkyl. In someembodiments is a compound of formula (III) wherein R¹² is —CF₃. In someembodiments is a compound of formula (III) wherein R¹² is —N(R⁶)₂. Insome embodiments is a compound of formula (III) wherein R¹² is —NH₂. Insome embodiments is a compound of formula (III) wherein R¹ is —N(H)CH₃.In some embodiments is a compound of formula (III) wherein R¹² is—N(CH₃)₂. In some embodiments is a compound of formula (III) wherein R¹²is —C₁₋₆alkyl-N(R⁶)₂. In some embodiments is a compound of formula (III)wherein R¹² is —CH₂N(R⁶)₂. In some embodiments is a compound of formula(III) wherein R¹² is —CH₂NH₂. In some embodiments is a compound offormula (III) wherein R¹² is —CH₂N(H)CH₃. In some embodiments is acompound of formula (III) wherein R¹² is —CH₂N(CH₃)₂. In someembodiments is a compound of formula (III) wherein R¹² is —CH₂CH₂N(R⁶)₂.In some embodiments is a compound of formula (III) wherein R¹² is—CH₂CH₂NH₂. In some embodiments is a compound of formula (III) whereinR¹² is —CH₂CH₂N(H)CH₃. In some embodiments is a compound of formula(III) wherein R¹² is —CH₂CH₂N(CH₃)₂. In some embodiments is a compoundof formula (III) wherein R¹² is —CH₂CH₂CH₂N(R⁶)₂. In some embodiments isa compound of formula (III) wherein R¹² is —CH₂CH₂NH₂. In someembodiments is a compound of formula (III) wherein R¹² is—CH₂CH₂CH₂N(H)CH₃. In some embodiments is a compound of formula (III)wherein R¹² is —CH₂CH₂CH₂N(CH₃)₂. In some embodiments is a compound offormula (III) wherein R¹² is —N(R⁶)₂ or —C₁₋₆alkyl-N(R⁶)₂. In someembodiments is a compound of formula (III) wherein R¹² is —C(O)N(R⁶)₂.In some embodiments is a compound of formula (III) wherein R¹² is—C(O)NH₂. In some embodiments is a compound of formula (III) wherein nis 3. In some embodiments is a compound of formula (III) wherein n is 2.In some embodiments is a compound of formula (III) wherein n is 1. Insome embodiments is a compound of formula (III) wherein n is 0. In someembodiments is a compound of formula (III) wherein n is 1 and R¹² ishalo. In some embodiments is a compound of formula (III) wherein n is 1and R¹² is —F. In some embodiments is a compound of formula (III)wherein n is 1 and R¹² is —Cl. In some embodiments is a compound offormula (III) wherein n is 1 and R¹² is C₁₋₆haloalkyl. In someembodiments is a compound of formula (III) wherein n is 1 and R¹² is—CF₃. In some embodiments is a compound of formula (III) wherein n is 1and R¹² is —N(R⁶)₂. In some embodiments is a compound of formula (III)wherein n is 1 and R¹² is —NH₂. In some embodiments is a compound offormula (III) wherein n is 1 and R¹² is —C(O)N(R⁶)₂. In some embodimentsis a compound of formula (III) wherein n is 1 and R¹² is —C(O)NH₂.

In some embodiments is a compound selected from:(R)-1-benzyl-N-(9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-2-yl)-1H-pyrazole-4-carboxamide;(R)—N-(1-(3-aminobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;(R)—N-(1-(2-aminobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;and(R)-1-(3-aminobenzyl)-N-(9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-2-yl)-1H-pyrazole-4-carboxamide;or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In another aspect is a compound of formula (IV) having the structure:

wherein:

is heterocyclyl;

-   R² is independently hydrogen, halo, C₁₋₆alkyl, or C₁₋₆haloalkyl;-   R^(4a) and R^(4b) are each independently hydrogen, halo, C₁₋₆alkyl,    or C₁₋₆haloalkyl; or R^(4a) and R^(4b) together with the carbon to    which they are both attached, form a cycloalkyl;-   each R⁶ is independently hydrogen or C₁₋₆alkyl;-   R¹¹ is halo, C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁶)₂, —C₁₋₆alkyl-N(R⁶)₂,    or —C(O)N(R⁶)₂;-   each R¹² is independently —OH, —CN, halo, C₁₋₆alkyl, C₁₋₆haloalkyl,    C₁₋₆alkoxy, C₁₋₆haloalkoxy, —N(R⁶)₂, —C₁₋₆alkyl-N(R⁶)₂, —C(O)R⁶,    —C(O)OR⁶, —C(O)N(R⁶)₂, aryl, aralkyl, cycloalkyl, heterocyclyl, or    heteroaryl; and-   n is 0, 1, 2, 3, or 4;-   as an individual stereoisomer, enantiomer or tautomer thereof or a    mixture thereof;-   or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In some embodiments is a compound of formula (IV) wherein R² ishydrogen. In some embodiments is a compound of formula (IV) wherein R²is halo. In some embodiments is a compound of formula (IV) wherein R² is—F. In some embodiments is a compound of formula (IV) wherein R² is —Cl.In some embodiments is a compound of formula (IV) wherein R² is C₁₋₆alkyl. In some embodiments is a compound of formula (IV) wherein R² is—CH₃. In some embodiments is a compound of formula (IV) wherein R² is—CH₂CH₃. In some embodiments is a compound of formula (IV) wherein R² is—CH(CH₃)₂. In some embodiments is a compound of formula (IV) wherein R²is C₁₋₆haloalkyl. In some embodiments is a compound of formula (IV)wherein R² is —CF₃.

In some embodiments is a compound of formula (IV) wherein R^(4a) ishydrogen. In some embodiments is a compound of formula (IV) whereinR^(4a) is halo. In some embodiments is a compound of formula (IV)wherein R^(4a) is —F. In some embodiments is a compound of formula (IV)wherein R^(4a) is —Cl. In some embodiments is a compound of formula (IV)wherein R^(4a) is C₁₋₆ alkyl. In some embodiments is a compound offormula (IV) wherein R^(4a) is —CH₃. In some embodiments is a compoundof formula (IV) wherein R^(4a) is —CH₂CH₃. In some embodiments is acompound of formula (IV) wherein R^(4a) is —CH(CH₃)₂. In someembodiments is a compound of formula (IV) wherein R^(4b) is hydrogen. Insome embodiments is a compound of formula (IV) wherein R^(4b) is halo.In some embodiments is a compound of formula (IV) wherein R^(4b) is —F.In some embodiments is a compound of formula (IV) wherein R^(4b) is —Cl.In some embodiments is a compound of formula (IV) wherein R^(4b) isC₁₋₆alkyl. In some embodiments is a compound of formula (IV) whereinR^(4b) is —CH₃. In some embodiments is a compound of formula (IV)wherein R^(4b) is —CH₂CH₃. In some embodiments is a compound of formula(IV) wherein R^(4b) is —CH(CH₃)₂. In some embodiments is a compound offormula (IV) wherein R^(4b) is C₁₋₆haloalkyl. In some embodiments is acompound of formula (IV) wherein R^(4b) is —CF₃. In some embodiments isa compound of formula (IV) wherein R^(4a) is C₁₋₆alkyl and R^(4b) ishydrogen. In some embodiments is a compound of formula (IV) whereinR^(4a) is —CH₃ and R^(4b) is hydrogen. In some embodiments is a compoundof formula (IV) wherein R^(4a) and R^(4b), together with the carbon towhich they are both attached, form a cycloalkyl. In some embodiments isa compound of formula (IV) wherein R^(4a) and R^(4b), together with thecarbon to which they are both attached, form a cyclopropyl. In someembodiments is a compound of formula (IV) wherein R^(4a) and R^(4b),together with the carbon to which they are both attached, form acyclobutyl. In some embodiments is a compound of formula (IV) whereinR^(4a) and R^(4b), together with the carbon to which they are bothattached, form a cyclopentyl. In some embodiments is a compound offormula (IV) wherein R^(4a) and R^(4b), together with the carbon towhich they are both attached, form a cyclohexyl.

In some embodiments is a compound of formula (IV) wherein each R¹² isindependently —OH, —CN, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy, —N(R⁶)₂, —C₁₋₆alkyl-N(R⁶)₂, —C(O)R⁶, —C(O)OR⁶, or—C(O)N(R⁶)₂. In some embodiments is a compound of formula (IV) whereineach R¹² is independently halo, C₁₋₆alkyl, —N(R⁶)₂, —C₁₋₆alkyl-N(R⁶)₂,or C₁₋₆haloalkyl. In some embodiments is a compound of formula (IV)wherein R¹² is halo. In some embodiments is a compound of formula (IV)wherein R¹² is —F. In some embodiments is a compound of formula (IV)wherein R¹² is —Cl. In some embodiments is a compound of formula (IV)wherein R¹² is C₁₋₆haloalkyl. In some embodiments is a compound offormula (IV) wherein R¹² is —CF₃. In some embodiments is a compound offormula (IV) wherein R¹² is —N(R⁶)₂. In some embodiments is a compoundof formula (IV) wherein R¹² is —NH₂. In some embodiments is a compoundof formula (IV) wherein R¹² is —C₁₋₆alkyl-N(R⁶)₂. In some embodiments isa compound of formula (IV) wherein R¹² is —CH₂N(R⁶)₂. In someembodiments is a compound of formula (IV) wherein R¹² is —CH₂NH₂. Insome embodiments is a compound of formula (IV) wherein R¹² is—C(O)N(R⁶)₂. In some embodiments is a compound of formula (IV) whereinR¹² is —C(O)NH₂. In some embodiments is a compound of formula (IV)wherein n is 3. In some embodiments is a compound of formula (IV)wherein n is 2. In some embodiments is a compound of formula (IV)wherein n is 1. In some embodiments is a compound of formula (IV)wherein n is 0. In some embodiments is a compound of formula (IV)wherein n is 1 and R¹² is halo. In some embodiments is a compound offormula (IV) wherein n is 1 and R¹² is —F. In some embodiments is acompound of formula (IV) wherein n is 1 and R¹² is —Cl. In someembodiments is a compound of formula (IV) wherein n is 1 and R¹² is C₁₋₆haloalkyl. In some embodiments is a compound of formula (IV) wherein nis 1 and R¹² is —CF₃. In some embodiments is a compound of formula (IV)wherein n is 1 and R¹² is —N(R⁶)₂. In some embodiments is a compound offormula (IV) wherein n is 1 and R¹² is —NH₂. In some embodiments is acompound of formula (IV) wherein n is 1 and R¹² is —C₁₋₆alkyl-N(R⁶)₂. Insome embodiments is a compound of formula (IV) wherein n is 1 and R¹² is—CH₂N(R⁶)₂. In some embodiments is a compound of formula (IV) wherein nis 1 and R¹² is —CH₂NH₂. In some embodiments is a compound of formula(IV) wherein n is 1 and R¹² is —C(O)N(R⁶)₂. In some embodiments is acompound of formula (IV) wherein n is 1 and R¹² is —C(O)NH₂.

In some embodiments is a compound of formula (IV) wherein R¹¹ is halo.In some embodiments is a compound of formula (IV) wherein R¹¹ is —F. Insome embodiments is a compound of formula (IV) wherein R¹¹ is —Cl. Insome embodiments is a compound of formula (IV) wherein R¹¹ isC₁₋₆haloalkyl. In some embodiments is a compound of formula (IV) whereinR¹¹ is —CF₃. In some embodiments is a compound of formula (IV) whereinR¹ is —N(R⁶)₂. In some embodiments is a compound of formula (IV) whereinR¹¹ is —NH₂. In some embodiments is a compound of formula (IV) whereinR¹¹ is —N(H)CH₃. In some embodiments is a compound of formula (IV)wherein R¹¹ is —N(CH₃)₂. In some embodiments is a compound of formula(IV) wherein R¹¹ is —C₁₋₆alkyl-N(R⁶)₂. In some embodiments is a compoundof formula (IV) wherein R¹¹ is —CH₂N(R⁶)₂. In some embodiments is acompound of formula (IV) wherein R¹¹ is —CH₂NH₂. In some embodiments isa compound of formula (IV) wherein R¹¹ is —CH₂N(H)CH₃. In someembodiments is a compound of formula (IV) wherein R¹ is —CH₂N(CH₃)₂. Insome embodiments is a compound of formula (IV) wherein R¹¹ is—CH₂CH₂N(R⁶)₂. In some embodiments is a compound of formula (IV) whereinR¹ is —CH₂CH₂NH₂. In some embodiments is a compound of formula (IV)wherein R¹¹ is —CH₂CH₂N(H)CH₃. In some embodiments is a compound offormula (IV) wherein R¹ is —CH₂CH₂N(CH₃)₂. In some embodiments is acompound of formula (IV) wherein R¹¹ is —CH₂CH₂CH₂N(R⁶)₂. In someembodiments is a compound of formula (IV) wherein R¹ is —CH₂CH₂CH₂NH₂.In some embodiments is a compound of formula (IV) wherein R¹¹ is—CH₂CH₂CH₂N(H)CH₃. In some embodiments is a compound of formula (IV)wherein R¹ is —CH₂CH₂CH₂N(CH₃)₂. In some embodiments is a compound offormula (IV) wherein R¹¹ is —N(R⁶)₂ or —C₁₋₆alkyl-N(R⁶)₂. In someembodiments is a compound of formula (IV) wherein R¹¹ is —C(O)N(R⁶)₂. Insome embodiments is a compound of formula (IV) wherein R¹¹ is —C(O)NH₂.In some embodiments is a compound of formula (IV) wherein R¹ is—C(O)N(H)CH₃. In some embodiments is a compound of formula (IV) whereinR¹¹ is —C(O)N(CH₃)₂.

In some embodiments is a compound of formula (IV) wherein

is piperidine. In some embodiments is a compound of formula (IV) wherein

is piperazine. In some embodiments is a compound of formula (IV) wherein

is morpholine. In some embodiments is a compound of formula (IV) wherein

is thiomorpholine. In some embodiments is a compound of formula (IV)wherein

is tetrahydropyran. In some embodiments is a compound of formula (IV)wherein

is pyrrolidine. In some embodiments is a compound of formula (IV)wherein

is tetrahydrofuran.

In some embodiments is a compound having the structure:(R)-9-methyl-N-(1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In some embodiments is a compound selected from:(R)-9-methyl-6-oxo-N-(1-(4-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;(R)—N-(1-(2,4-difluorobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;and(R)—N-(1-benzyl-1H-pyrazol-4-yl)-5-chloro-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In some embodiments is a compound having the structure:(R)—N-(1-(4-(aminomethyl)benzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In some embodiments is a compound having the structure:(R)—N-(1-(4-(aminomethyl)benzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamidehydrochloride salt; or a pharmaceutically acceptable solvate or prodrugthereof.

In some embodiments is a compound having the structure:(R)—N-(1-(4-aminobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In some embodiments is a compound having the structure:(R)—N-(1-(4-aminobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamidehydrochloride salt; or a pharmaceutically acceptable solvate or prodrugthereof.

In some embodiments is a compound having the structure:(R)—N-(2-carbamoylphenyl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

Utility and Testing of the Compounds of the Invention

This invention is directed to compounds which inhibit RSK proteins bycompeting for ATP in the N-terminal kinase domain. As referred toherein, RSK refers to all known isoforms of RSK, including RSK1, RSK2,RSK3 and RSK4. In particular, the compounds described herein weredesigned to block RSK activity. The compounds are therefore useful intreating diseases and conditions which are associated with RSK activity,including the activity of the individual isoforms or any combinationthereof.

The compounds described herein were also designed for direct cellularuptake and adaptability for the development of antibody drug conjugates.In addition, the compounds described herein were synthesized to informthe structure activity relationship of these RSK inhibitors. There was agood correlation between kinase inhibition in vitro and growthsuppression in vivo based on crystal violet staining, Alamar Blue andsoft agar assays.

The models used were cancer cell lines derived from human and murinesources, as set forth below in Table 1A and Table 1B:

TABLE 1A Cell Sub- Site of Molecular Line type Species Age Origin TumourType Classification Additional Details MDA- TN Human 51 PleuralAdenocarcinoma Basal B P53 Mutation; BRCA1 WT; MB-231 Effusion KRASMutation; Gefitinib Insensitive MDA- TN Human 51 Pleural AdenocarcinomaBasal A P53 Mutation; BRCA1 WT; MB-468 Effusion Amplified EGFR SUM149 TNHuman N/A Pleural Inflammatory Basal B P53 Mutation; BRCA1 Mutant;Effusion Ductal Carcinoma Gefitinib Sensitiv

SUM149- TN Human N/A Pleural Inflammatory Basal B P53 Mutation; BRCA1Mutant; PTXR Effusion Ductal Carcinoma Paclitaxel Resista

MDA- TN Human 31 Pleural Invasive Ductal Basal B P53 Mutation; MB-435Effusion Carcinoma BRCA1 WT HCC1143 TN Human 52 Primary Ductal CarcinomaBasal A P53 Mutation; Tumour BRCA1 WT 4T1 TN Mouse N/A Primary CarcinomaBasal-Like Metastatic TNBC Model; Tumour Paclitaxel Resistant T47D ER/Human 54 Pleural Invasive Ductal Luminal A Hormone Responsive PREffusion Carcinoma

indicates data missing or illegible when filed

TABLE 1B Cell Sub- Site of Tumour Molecular Line type Species Age OriginType Classification Additional Details HCC1937 TN Human 23 PrimaryDuctal Basal A P53 Mutation; BRCA1 Tumour Carcinoma Mutant; PTEN Deletic

JIMT-1 HER2 Human 62 Pleural Invasive ERBB2 Herceptin Resistant EffusionDuctal Carcinoma PC3 Prostate Human 62 Bone Adeno- SCNC No AndrogenReceptor Metastasis carcinoma (AR) or Prostaste Spe

Antigen (PSA) Expression

indicates data missing or illegible when filed

Compounds described herein demonstrated activity in these TNBC celllines which harboured mutations, p53 mutation, amplification ofepidermal growth factor receptors as well as those that were drugresistant. Despite the diverse genetic composition of TNBC, thecompounds described herein were uniformly active in suppressing cancercell growth.

The compounds are therefore useful for suppressing RSK activity, cancercell growth, metabolism, cell signalling, and for promoting cell death.The potency of the compounds in inhibiting the activity of RSK can beassessed directly using a cell-free kinase assay with human recombinantRSK. The specificity of the inhibitors for RSK can be addressed byevaluating the small molecules in assays containing other kinases thatare structurally related, such as MK2 (Mitogen-activated proteinkinase-activated protein kinase 2). Cell growth can be measured usingDNA stains such as crystal violet. Metabolism is altered by RSKinhibitors and can be assessed using Alamar Blue. The mammosphere assayis a convenient means to measure the way in which RSK inhibitors blockself-renewal. There are several RSK substrates in cancer, however themost reliable marker for RSK inactivation is through the loss ofphosphorylated Y-box binding protein-1 (P-YB-1S102). RSK inhibitors willtrigger cell death in cancer cells that can be assessed by a number ofmethods including PARP cleavage. The safety of RSK inhibitors can beassessed using a colony formation assay with CD34+ cells. CD34+ cellsare primary bone marrow progenitor cells. They can be induced todifferentiate into mature eurythocytes and monocytes using definedmedia.

In some embodiments of the methods of using the compounds of formula(I), (II), (III), or (IV) as described herein, is a method of treating adisease or condition associated with RSK activity in a mammal, whereinthe method comprises administering to the mammal a therapeuticallyeffective amount of a compound of formula (I), (II), (III), or (IV) asan individual stereoisomer, enantiomer or tautomer thereof or a mixturethereof; or a pharmaceutically acceptable salt, solvate, or prodrugthereof. In some embodiments is a method of treating a disease orcondition associated with p90 ribosomal S6 kinase (RSK) activity in amammal, wherein the method comprises administering to the mammal atherapeutically effective amount of a compound of formula (I), (II),(III), or (IV) as an individual stereoisomer, enantiomer or tautomerthereof or a mixture thereof; or a pharmaceutically acceptable salt,solvate, or prodrug thereof. In some embodiments is a method of treatinga disease or condition associated with p90 ribosomal S6 kinase (RSK)activity in a mammal, wherein the method comprises administering to themammal a therapeutically effective amount of a compound of formula (I),(II), (III), or (IV) as an individual stereoisomer, enantiomer ortautomer thereof or a mixture thereof; or a pharmaceutically acceptablesalt, solvate, or prodrug thereof; wherein the disease or condition iscancer. In some embodiments is a method of treating cancer in a mammal,wherein the method comprises administering to the mammal atherapeutically effective amount of a compound of formula (I), (II),(III), or (IV) as an individual stereoisomer, enantiomer or tautomerthereof or a mixture thereof; or a pharmaceutically acceptable salt,solvate, or prodrug thereof; wherein the cancer is breast cancer,prostate cancer, lung cancer, brain cancer, skin cancer, bone cancer,ovarian cancer, or a blood cancer. In some embodiments is a method oftreating prostate cancer in a mammal, wherein the method comprisesadministering to the mammal a therapeutically effective amount of acompound of formula (I), (II), (III), or (IV) as an individualstereoisomer, enantiomer or tautomer thereof or a mixture thereof; or apharmaceutically acceptable salt, solvate, or prodrug thereof. In someembodiments is a method of treating lung cancer in a mammal, wherein themethod comprises administering to the mammal a therapeutically effectiveamount of a compound of formula (I), (II), (III), or (IV) as anindividual stereoisomer, enantiomer or tautomer thereof or a mixturethereof; or a pharmaceutically acceptable salt, solvate, or prodrugthereof. In some embodiments is a method of treating brain cancer in amammal, wherein the method comprises administering to the mammal atherapeutically effective amount of a compound of formula (I), (II),(III), or (IV) as an individual stereoisomer, enantiomer or tautomerthereof or a mixture thereof; or a pharmaceutically acceptable salt,solvate, or prodrug thereof. In some embodiments is a method of treatingskin cancer in a mammal, wherein the method comprises administering tothe mammal a therapeutically effective amount of a compound of formula(I), (II), (III), or (IV) as an individual stereoisomer, enantiomer ortautomer thereof or a mixture thereof; or a pharmaceutically acceptablesalt, solvate, or prodrug thereof. In some embodiments is a method oftreating bone cancer in a mammal, wherein the method comprisesadministering to the mammal a therapeutically effective amount of acompound of formula (I), (II), (III), or (IV) as an individualstereoisomer, enantiomer or tautomer thereof or a mixture thereof; or apharmaceutically acceptable salt, solvate, or prodrug thereof. In someembodiments is a method of treating ovarian cancer in a mammal, whereinthe method comprises administering to the mammal a therapeuticallyeffective amount of a compound of formula (I), (II), (III), or (IV) asan individual stereoisomer, enantiomer or tautomer thereof or a mixturethereof; or a pharmaceutically acceptable salt, solvate, or prodrugthereof. In some embodiments is a method of treating a blood cancer in amammal, wherein the method comprises administering to the mammal atherapeutically effective amount of a compound of formula (I), (II),(III), or (IV) as an individual stereoisomer, enantiomer or tautomerthereof or a mixture thereof; or a pharmaceutically acceptable salt,solvate, or prodrug thereof. In some embodiments is a method of treatingbreast cancer in a mammal, wherein the method comprises administering tothe mammal a therapeutically effective amount of a compound of formula(I), (II), (III), or (IV) as an individual stereoisomer, enantiomer ortautomer thereof or a mixture thereof; or a pharmaceutically acceptablesalt, solvate, or prodrug thereof. In some embodiments is a method oftreating breast cancer in a mammal, wherein the method comprisesadministering to the mammal a therapeutically effective amount of acompound of formula (I), (II), (III), or (IV) as an individualstereoisomer, enantiomer or tautomer thereof or a mixture thereof; or apharmaceutically acceptable salt, solvate, or prodrug thereof; whereinthe breast cancer is selected from Luminal A, Luminal B, Her-2 positive,triple-negative breast cancer, basal-like breast cancer, inflammatorybreast cancer, BRCA1/2 mutated breast cancer, drug resistant breastcancer, murine breast cancer, gefitinib insensitive: MDA-MB-231, andmetastatic breast cancer.

Specific embodiments of the methods described herein, including thesuitable conditions for each of the above described embodiments, aredescribed in more detail below in the following sections.

Combination Treatments

In some embodiments, the compounds of formula (I), (II), (III), or (IV)described herein, and compositions thereof, are used in combination withother therapeutic agents that are selected for their therapeutic valuefor the condition to be treated. In general, the compositions describedherein and, in embodiments where combinational therapy is employed,other agents do not have to be administered in the same pharmaceuticalcomposition, and may, because of different physical and chemicalcharacteristics, have to be administered by different routes. Thedetermination of the mode of administration and the advisability ofadministration, where possible, in the same pharmaceutical composition,is well within the knowledge of the clinician. The initialadministration can be made according to established protocols recognizedin the field, and then, based upon the observed effects, the dosage,modes of administration and times of administration can be modified bythe clinician.

In some embodiments, it is appropriate to administer at least onecompound described herein in combination with another therapeutic agent.By way of example only, if one of the side effects experienced by apatient upon receiving one of the compounds herein, such as a compoundof formula (I), (II), (III), or (IV), is nausea, then it may beappropriate to administer an anti-nausea agent in combination with theinitial therapeutic agent. Or, by way of example only, the therapeuticeffectiveness of one of the compounds described herein may be enhancedby administration of an adjuvant (i.e., by itself the adjuvant may haveminimal therapeutic benefit, but in combination with another therapeuticagent, the overall therapeutic benefit to the patient is enhanced). Or,by way of example only, the benefit experienced by a patient may beincreased by administering one of the compounds described herein withanother therapeutic agent (which also includes a therapeutic regimen)that also has therapeutic benefit. In any case, regardless of thedisease, disorder or condition being treated, the overall benefitexperienced by the patient may simply be additive of the two therapeuticagents or the patient may experience a synergistic benefit.

For therapeutic applications, in some embodiments the compounds or drugsof the present invention are administered alone or co-administered incombination with conventional chemotherapy, radiotherapy, hormonaltherapy, and/or immunotherapy.

As a non-limiting example, in some embodiments the compounds of formula(I), (II), (III), or (IV) described herein are co-administered withconventional chemotherapeutic agents including alkylating agents (e.g.,cyclophosphamide, ifosfamide, chlorambucil, busulfan, melphalan,mechlorethamine, uramustine, thiotepa, nitrosoureas, etc.),anti-metabolites (e.g., 5-fluorouracil, azathioprine, methotrexate,leucovorin, capecitabine, cytarabine, floxuridine, fludarabine,gemcitabine, pemetrexed, raltitrexed, etc.), plant alkaloids (e.g.,vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin,paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g.,irinotecan, topotecan, amsacrine, etoposide (VP16), etoposide phosphate,teniposide, etc.), antitumor antibiotics (e.g., doxorubicin, adriamycin,daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin,mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g.cisplatin, oxaloplatin, carboplatin, etc.), and the like.

In some embodiments, the compounds of formula (I), (II), (III), or (IV)described herein are co-administered with conventional hormonaltherapeutic agents including, but not limited to, steroids (e.g.,dexamethasone), finasteride, aromatase inhibitors, tamoxifen, andgonadotropin-releasing hormone agonists (GnRH) such as goserelin.

In some embodiments, the compounds of formula (I), (II), (III), or (IV)described herein are co-administered with conventional immunotherapeuticagents including, but not limited to, immunostimulants (e.g., BacillusCalmette-Guérin (BCG), levamisole, interleukin-2, alpha-interferon,etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52,anti-HLA-DR, and anti-VEGF monoclonal antibodies), immunotoxins (e.g.,anti-CD33 monoclonal antibody-calicheamicin conjugate, anti-CD22monoclonal antibody-pseudomonas exotoxin conjugate, etc.), andradioimmunotherapy (e.g., anti-CD20 monoclonal antibody conjugated to¹¹¹In, ⁹⁰Y, or ¹³¹I, etc.).

In further embodiments, the compounds of formula (I), (II), (III), or(IV) described herein are co-administered with a poly ADP-ribosepolymerase (PARP) inhibitor, STAT 3 inhibitor, Janus Kinase inhibitor,or EGFR inhibitor.

The particular choice of compounds used will depend upon the diagnosisof the attending physicians and their judgment of the condition of thepatient and the appropriate treatment protocol. In some embodiments, thecompounds are administered concurrently (e.g., simultaneously,essentially simultaneously or within the same treatment protocol) orsequentially, depending upon the nature of the disease, disorder, orcondition, the condition of the patient, and the actual choice ofcompounds used. The determination of the order of administration, andthe number of repetitions of administration of each therapeutic agentduring a treatment protocol, is well within the knowledge of thephysician after evaluation of the disease being treated and thecondition of the patient.

Therapeutically-effective dosages can vary when the drugs are used intreatment combinations. Methods for experimentally determiningtherapeutically-effective dosages of drugs and other agents for use incombination treatment regimens are described in the literature. Forexample, the use of metronomic dosing, i.e., providing more frequent,lower doses in order to minimize toxic side effects, has been describedextensively in the literature Combination treatment further includesperiodic treatments that start and stop at various times to assist withthe clinical management of the patient.

For combination therapies described herein, dosages of theco-administered compounds will of course vary depending on the type ofco-drug employed, on the specific drug employed, on the disease orcondition being treated and so forth. In addition, when co-administeredwith one or more biologically active agents, the compound providedherein may be administered either simultaneously with the biologicallyactive agent(s), or sequentially. If administered sequentially, theattending physician will decide on the appropriate sequence ofadministering protein in combination with the biologically activeagent(s).

In any case, the multiple therapeutic agents (one of which is a compoundof formula (I), (II), (III), or (IV) described herein) may beadministered in any order or even simultaneously. If simultaneously, themultiple therapeutic agents may be provided in a single, unified form,or in multiple forms (by way of example only, either as a single pill oras two separate pills). One of the therapeutic agents may be given inmultiple doses, or both may be given as multiple doses. If notsimultaneous, the timing between the multiple doses may vary from morethan zero weeks to less than four weeks. In addition, the combinationmethods, compositions and formulations are not to be limited to the useof only two agents; the use of multiple therapeutic combinations arealso envisioned.

It is understood that the dosage regimen to treat, prevent, orameliorate the condition(s) for which relief is sought, can be modifiedin accordance with a variety of factors. These factors include thedisorder or condition from which the subject suffers, as well as theage, weight, sex, diet, and medical condition of the subject. Thus, thedosage regimen actually employed can vary widely and therefore candeviate from the dosage regimens set forth herein.

The pharmaceutical agents which make up the combination therapydisclosed herein may be a combined dosage form or in separate dosageforms intended for substantially simultaneous administration. Thepharmaceutical agents that make up the combination therapy may also beadministered sequentially, with either therapeutic compound beingadministered by a regimen calling for two-step administration. Thetwo-step administration regimen may call for sequential administrationof the active agents or spaced-apart administration of the separateactive agents. The time period between the multiple administration stepsmay range from, a few minutes to several hours, depending upon theproperties of each pharmaceutical agent, such as potency, solubility,bioavailability, plasma half-life and kinetic profile of thepharmaceutical agent. Circadian variation of the target moleculeconcentration may also determine the optimal dose interval.

In some embodiments, the compounds described herein are used incombination with procedures that may provide additional or synergisticbenefit to the patient. In some embodiments, the compounds of formula(I), (II), (III), or (IV) described herein are administered withradiation therapy. By way of example only, patients are expected to findtherapeutic and/or prophylactic benefit in the methods described herein,wherein pharmaceutical composition of a compound disclosed herein and/orcombinations with other therapeutics are combined with genetic testingto determine whether that individual is a carrier of a mutant gene thatis known to be correlated with certain diseases or conditions.

The compounds described herein and combination therapies areadministered before, during or after the occurrence of a disease orcondition, and the timing of administering the composition containing acompound can vary. Thus, for example, in some embodiments the compoundsare used as a prophylactic and are administered continuously to subjectswith a propensity to develop conditions or diseases in order to preventthe occurrence of the disease or condition. In some embodiments, thecompounds and compositions can be administered to a subject during or assoon as possible after the onset of the symptoms. In some embodiments,the administration of the compounds is initiated within the first 48hours of the onset of the symptoms, preferably within the first 48 hoursof the onset of the symptoms, more preferably within the first 6 hoursof the onset of the symptoms, and most preferably within 3 hours of theonset of the symptoms. The initial administration can be via any routepractical, such as, for example, an intravenous injection, a bolusinjection, infusion over about 5 minutes to about 5 hours, a pill, acapsule, transdermal patch, buccal delivery, and the like, orcombination thereof. A compound is preferably administered as soon as ispracticable after the onset of a disease or condition is detected orsuspected, and for a length of time necessary for the treatment of thedisease, such as, for example, from 1 day to about 3 months. The lengthof treatment can vary for each subject, and the length can be determinedusing the known criteria. For example, the compound or a formulationcontaining the compound can be administered for at least 2 weeks,preferably about 1 month to about 5 years.

Pharmaceutical Compositions of the Invention and Administration

The present invention also relates to pharmaceutical compositioncontaining the compounds disclosed herein. In one embodiment, thepresent invention relates to a composition comprising compoundsdescribed herein in a pharmaceutically acceptable carrier, excipient ordiluent and in an amount effective to inhibit the activity of RSK whenadministered to an animal, preferably a mammal, most preferably a humanpatient.

In some embodiments is a pharmaceutical composition comprising acompound of formula (I), (II), (III), or (IV) as an individualstereoisomer, enantiomer or tautomer thereof or a mixture thereof; or apharmaceutically acceptable salt, solvate, or prodrug thereof, and atleast one pharmaceutically acceptable excipient. In some embodiments isa pharmaceutical composition comprising a compound of formula (I) as anindividual stereoisomer, enantiomer or tautomer thereof or a mixturethereof; or a pharmaceutically acceptable salt, solvate, or prodrugthereof, and at least one pharmaceutically acceptable excipient. In someembodiments is a pharmaceutical composition comprising a compound offormula (II) as an individual stereoisomer, enantiomer or tautomerthereof or a mixture thereof; or a pharmaceutically acceptable salt,solvate, or prodrug thereof, and at least one pharmaceuticallyacceptable excipient. In some embodiments is a pharmaceuticalcomposition comprising a compound of formula (III) as an individualstereoisomer, enantiomer or tautomer thereof or a mixture thereof; or apharmaceutically acceptable salt, solvate, or prodrug thereof, and atleast one pharmaceutically acceptable excipient.

A pharmaceutical composition, as used herein, refers to a mixture of acompound of formula (I), (II), (III), or (IV) described herein, withother chemical components, such as carriers, stabilizers, diluents,dispersing agents, suspending agents, thickening agents, and/orexcipients. The pharmaceutical composition facilitates administration ofthe compound to an organism. In practicing the methods of treatment oruse provided herein, therapeutically effective amounts of compoundsdescribed herein are administered in a pharmaceutical composition to amammal having a disease, disorder, or condition to be treated. In someembodiments, the mammal is a human. A therapeutically effective amountcan vary widely depending on the severity of the disease, the age andrelative health of the subject, the potency of the compound used andother factors. The compounds of formula (I), (II), (III), or (IV) can beused singly or in combination with one or more therapeutic agents ascomponents of mixtures (as in combination therapy).

Administration of the compounds described herein, or theirpharmaceutically acceptable salts, in pure form or in an appropriatepharmaceutical composition, can be carried out via any of the acceptedmodes of administration of agents for serving similar utilities. Thepharmaceutical compositions described herein can be prepared bycombining a compound described herein with an appropriatepharmaceutically acceptable carrier, diluent or excipient, and may beformulated into preparations in solid, semi-solid, liquid or gaseousforms, such as tablets, capsules, powders, granules, ointments,solutions, suppositories, injections, inhalants, gels, microspheres, andaerosols. Typical routes of administering such pharmaceuticalcompositions include, without limitation, oral, topical, transdermal,inhalation, parenteral, sublingual, rectal, vaginal, and intranasal. Theterm “parenteral” as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection or infusiontechniques. Pharmaceutical compositions described herein are formulatedso as to allow the active ingredients contained therein to bebioavailable upon administration of the composition to a patient.Compositions that will be administered to a subject or patient take theform of one or more dosage units, where for example, a tablet may be asingle dosage unit, and a container of a compound described herein inaerosol form may hold a plurality of dosage units. Actual methods ofpreparing such dosage forms are known, or will be apparent, to thoseskilled in this art; for example, see The Science and Practice ofPharmacy, 20th Edition (Philadelphia College of Pharmacy and Science,2000). The composition to be administered will, in any event, contain atherapeutically effective amount of a compound described herein, or apharmaceutically acceptable salt thereof, for treatment of a disease orcondition of interest in accordance with the teachings of thisinvention.

The pharmaceutical compositions useful herein also contain apharmaceutically acceptable carrier, including any suitable diluent orexcipient, which includes any pharmaceutical agent that does not itselfinduce the production of antibodies harmful to the individual receivingthe composition, and which may be administered without undue toxicity.Pharmaceutically acceptable carriers include, but are not limited to,liquids, such as water, saline, glycerol and ethanol, and the like. Athorough discussion of pharmaceutically acceptable carriers, diluents,and other excipients is presented in REMINGTON'S PHARMACEUTICAL SCIENCES(Mack Pub. Co., N.J. current edition).

In some embodiments, a pharmaceutical composition described herein is inthe form of a solid or liquid. In one aspect, the carrier(s) areparticulate, so that the compositions are, for example, in tablet orpowder form. In some embodiments, the carrier(s) is liquid, with thecompositions being, for example, an oral syrup, injectable liquid or anaerosol, which is useful in, for example, inhalatory administration.

When intended for oral administration, the pharmaceutical composition ispreferably in either solid or liquid form, where semi-solid,semi-liquid, suspension and gel forms are included within the formsconsidered herein as either solid or liquid.

In some embodiments, as a solid composition for oral administration, thepharmaceutical composition is formulated into a powder, granule,compressed tablet, pill, capsule, chewing gum, wafer or the like form.Such a solid composition will typically contain one or more inertdiluents or edible carriers. In some embodiments, one or more of thefollowing is present: binders such as carboxymethylcellulose, ethylcellulose, microcrystalline cellulose, gum tragacanth or gelatin;excipients such as starch, lactose or dextrins, disintegrating agentssuch as alginic acid, sodium alginate, Primogel, corn starch and thelike; lubricants such as magnesium stearate or Sterotex; glidants suchas colloidal silicon dioxide; sweetening agents such as sucrose orsaccharin; a flavoring agent such as peppermint, methyl salicylate ororange flavoring; and a coloring agent.

When the pharmaceutical composition is in the form of a capsule, forexample, a gelatin capsule, it may contain, in addition to materials ofthe above type, a liquid carrier such as polyethylene glycol or oil.

In some embodiments, the pharmaceutical composition is in the form of aliquid, for example, an elixir, syrup, solution, emulsion or suspension.In some embodiments, the liquid is for oral administration or fordelivery by injection, as two examples. When intended for oraladministration, preferred composition contain, in addition to thepresent compounds, one or more of a sweetening agent, preservatives,dye/colorant and flavor enhancer. In some embodiments, in a compositionintended to be administered by injection, one or more of a surfactant,preservative, wetting agent, dispersing agent, suspending agent, buffer,stabilizer and isotonic agent is included.

The liquid pharmaceutical compositions described herein, whether they besolutions, suspensions or other like form, may include one or more ofthe following adjuvants: sterile diluents such as water for injection,saline solution, preferably physiological saline, Ringer's solution,isotonic sodium chloride, fixed oils such as synthetic mono ordiglycerides which may serve as the solvent or suspending medium,polyethylene glycols, glycerin, propylene glycol or other solvents;antibacterial agents such as benzyl alcohol or methyl paraben;antioxidants such as ascorbic acid or sodium bisulfite; chelating agentssuch as ethylenediaminetetraacetic acid; buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose. The parenteral preparation can be enclosedin ampoules, disposable syringes or multiple dose vials made of glass orplastic. Physiological saline is a preferred adjuvant. An injectablepharmaceutical composition is preferably sterile.

A liquid pharmaceutical composition described herein intended for eitherparenteral or oral administration should contain an amount of a compounddescribed herein such that a suitable dosage will be obtained.Typically, this amount is at least 0.01% of a compound described hereinin the composition. When intended for oral administration, this amountmay be varied to be between 0.1 and about 70% of the weight of thecomposition. Preferred oral pharmaceutical compositions contain betweenabout 4% and about 50% of the compound described herein. Preferredpharmaceutical compositions and preparations according to the presentinvention are prepared so that a parenteral dosage unit contains between0.01 to 10% by weight of the compound prior to dilution describedherein.

In some embodiments, the pharmaceutical composition described herein isintended for topical administration, in which case the carrier maysuitably comprise a solution, emulsion, ointment or gel base. The base,for example, may comprise one or more of the following: petrolatum,lanolin, polyethylene glycols, bee wax, mineral oil, diluents such aswater and alcohol, and emulsifiers and stabilizers. In some embodiments,thickening agents are present in a pharmaceutical composition fortopical administration. In some embodiments intended for transdermaladministration, the composition includes a transdermal patch oriontophoresis device. In some embodiments, topical formulations containa concentration of the compound described herein from about 0.1 to about10% w/v (weight per unit volume).

In some embodiments, the pharmaceutical composition described herein isintended for rectal administration, in the form, for example, of asuppository, which will melt in the rectum and release the drug. Thecomposition for rectal administration may contain an oleaginous base asa suitable nonirritating excipient. Such bases include, withoutlimitation, lanolin, cocoa butter and polyethylene glycol.

The pharmaceutical composition described herein may include variousmaterials, which modify the physical form of a solid or liquid dosageunit. For example, the composition may include materials that form acoating shell around the active ingredients. In some embodiments, thematerials that form the coating shell are typically inert, and areselected from, for example, sugar, shellac, and other enteric coatingagents. Alternatively, in some embodiments, the active ingredients isencased in a gelatin capsule.

The pharmaceutical composition described herein in solid or liquid formmay include an agent that binds to the compound described herein andthereby assists in the delivery of the compound. Suitable agents thatmay act in this capacity include a monoclonal or polyclonal antibody, aprotein or a liposome.

The pharmaceutical composition described herein may consist of dosageunits that can be administered as an aerosol. The term aerosol is usedto denote a variety of systems ranging from those of colloidal nature tosystems consisting of pressurized packages. In some embodiments,delivery is by a liquefied or compressed gas or by a suitable pumpsystem that dispenses the active ingredients. In some embodiments,aerosols of compounds described herein are delivered in single phase,bi-phasic, or tri-phasic systems in order to deliver the activeingredient(s). Delivery of the aerosol includes the necessary container,activators, valves, subcontainers, and the like, which together may forma kit. One skilled in the art, without undue experimentation maydetermine preferred aerosols.

In some embodiments, the pharmaceutical compositions described hereinare prepared by methodology well known in the pharmaceutical art. Forexample, in some embodiments, a pharmaceutical composition intended tobe administered by injection is prepared by combining a compounddescribed herein with sterile, distilled water so as to form a solution.In some embodiments, a surfactant is added to facilitate the formationof a homogeneous solution or suspension. Surfactants are compounds thatnon-covalently interact with the compound described herein so as tofacilitate dissolution or homogeneous suspension of the compound in theaqueous delivery system.

In some embodiments, the pharmaceutical compositions described hereinare formulated so as to provide quick, sustained or delayed release ofthe active ingredient after administration to the patient by employingprocedures known in the art. Controlled release drug delivery systemsinclude osmotic pump systems and dissolutional systems containingpolymer-coated reservoirs or drug-polymer matrix formulations. Examplesof controlled release systems are given in U.S. Pat. Nos. 3,845,770 and4,326,525 and in P. J. Kuzma et al., Regional Anesthesia 22 (6): 543-551(1997), all of which are incorporated herein by reference.

In some embodiments, the pharmaceutical compositions described hereinare delivered through intra-nasal drug delivery systems for local,systemic, and nose-to-brain medical therapies. Controlled ParticleDispersion (CPD)™ technology, traditional nasal spray bottles, inhalersor nebulizers are known by those skilled in the art to provide effectivelocal and systemic delivery of drugs by targeting the olfactory regionand paranasal sinuses.

In some embodiments, the pharmaceutical compositions described hereinalso relate to an intravaginal shell or core drug delivery devicesuitable for administration to the human or animal female. In someembodiments, the device is comprised of the active pharmaceuticalingredient in a polymer matrix, surrounded by a sheath, and capable ofreleasing the compound in a substantially zero order pattern on a dailybasis similar to devises used to apply testosterone as described in PCTPublished Patent Application No. WO 98/50016.

Current methods for ocular delivery include topical administration (eyedrops), subconjunctival injections, periocular injections, intravitrealinjections, surgical implants and iontophoresis (uses a small electricalcurrent to transport ionized drugs into and through body tissues). Thoseskilled in the art would combine the best suited excipients with thecompound for safe and effective intra-occular administration.

The most suitable route will depend on the nature and severity of thecondition being treated. Those skilled in the art are also familiar withdetermining administration methods (e.g., oral, intravenous, inhalation,sub-cutaneous, rectal etc.), dosage forms, suitable pharmaceuticalexcipients and other matters relevant to the delivery of the compoundsto a subject in need thereof.

Methods of Dosing and Treatment Regimens

The compounds described herein can be used in the preparation ofmedicaments for the treatment of cancer, or for the treatment ofdiseases or conditions that would benefit, at least in part, from RSKinhibition. In addition, a method for treating any of the diseases orconditions described herein in a subject in need of such treatment,involves administration of pharmaceutical compositions containing atleast one compound described herein, or a pharmaceutically acceptablesalt, pharmaceutically acceptable prodrug, or pharmaceuticallyacceptable solvate thereof, in therapeutically effective amounts to saidsubject.

The compounds described herein, or their pharmaceutically acceptablesalts, are administered in a therapeutically effective amount, whichwill vary depending upon a variety of factors including the activity ofthe specific compound employed; the metabolic stability and length ofaction of the compound; the age, body weight, general health, sex, anddiet of the patient; the mode and time of administration; the rate ofexcretion; the drug combination; the severity of the particular disorderor condition; and the subject undergoing therapy. Generally, atherapeutically effective daily dose is (for a 70 Kg mammal) from about0.001 mg/Kg (i.e., 0.07 mg) to about 100 mg/Kg (i.e., 7.0 g); preferablya therapeutically effective dose is (for a 70 Kg mammal) from about 0.01mg/Kg (i.e., 0.7 mg) to about 50 mg/Kg (i.e., 3.5 g); more preferably atherapeutically effective dose is (for a 70 Kg mammal) from about 1mg/kg (i.e., 70 mg) to about 25 mg/Kg (i.e., 1.75 g). In someembodiments, the daily dosages appropriate for the compounds describedherein described herein are from about 0.01 mg/kg to about 20 mg/kg. Insome embodiments, the daily dosages are from about 0.1 mg/kg to about 10mg/kg. An indicated daily dosage in the larger mammal, including, butnot limited to, humans, is in the range from about 0.5 mg to about 1000mg, conveniently administered in a single dose or in divided doses,including, but not limited to, up to four times a day or in extendedrelease form. In some embodiments, suitable unit dosage forms for oraladministration include from about 1 to about 500 mg active ingredient.In some embodiments, the unit dosage is about 1 mg, about 5 mg, about,10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 250mg, about 400 mg, or about 500 mg.

The ranges of effective doses provided herein are not intended to belimiting and represent preferred dose ranges. Such dosages may bealtered depending on a number of variables, not limited to the activityof the compound used, the disease or condition to be treated, the modeof administration, the requirements of the individual subject, theseverity of the disease or condition being treated, and the judgment ofthe practitioner. However, the most preferred dosage will be tailored tothe individual subject, as is understood and determinable by one skilledin the relevant arts. (see, e.g., Berkow et al., eds., The Merck Manual,16^(th) edition, Merck and Co., Rahway, N.J., 1992; Goodmanetna., eds.,Goodman and Cilman's The Pharmacological Basis of Therapeutics, 10^(th)edition, Pergamon Press, Inc., Elmsford, N.Y., (2001); Avery's DrugTreatment: Principles and Practice of Clinical Pharmacology andTherapeutics, 3rd edition, ADIS Press, LTD., Williams and Wilkins,Baltimore, Md. (1987), Ebadi, Pharmacology, Little, Brown and Co.,Boston, (1985); Osolci al., eds., Remington's Pharmaceutical Sciences,18^(th) edition, Mack Publishing Co., Easton, Pa. (1990); Katzung, Basicand Clinical Pharmacology, Appleton and Lange, Norwalk, Conn. (1992)).

The total dose required for each treatment can be administered bymultiple doses or in a single dose over the course of the day, ifdesired. Generally, treatment is initiated with smaller dosages, whichare less than the optimum dose of the compound. Thereafter, the dosageis increased by small increments until the optimum effect under thecircumstances is reached. The diagnostic pharmaceutical compound orcomposition can be administered alone or in conjunction with otherdiagnostics and/or pharmaceuticals directed to the pathology, ordirected to other symptoms of the pathology. The recipients ofadministration of compounds and/or compositions described herein can beany vertebrate animal, such as mammals. Among mammals, the preferredrecipients are mammals of the Orders Primate (including humans, apes andmonkeys), Arteriodactyla (including horses, goats, cows, sheep, pigs),Rodenta (including mice, rats, rabbits, and hamsters), and Carnivora(including cats, and dogs). Among birds, the preferred recipients areturkeys, chickens and other members of the same order. The mostpreferred recipients are humans.

The compositions containing the compound(s) described herein can beadministered for prophylactic and/or therapeutic treatments. Intherapeutic applications, the compositions are administered to a patientalready suffering from a disease or condition, in an amount sufficientto cure or at least partially arrest the symptoms of the disease orcondition. Amounts effective for this use will depend on the severityand course of the disease or condition, previous therapy, the patient'shealth status, weight, and response to the drugs, and the judgment ofthe treating physician.

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. When used in a patient, effectiveamounts for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician.

In the case wherein the patient's condition does not improve, upon thedoctor's discretion the administration of the compounds, in someembodiments, is administered chronically, that is, for an extendedperiod of time, including throughout the duration of the patient's lifein order to ameliorate or otherwise control or limit the symptoms of thepatient's disease or condition.

In the case wherein the patient's status does improve, upon the doctor'sdiscretion the administration of the compounds, in some embodiments, isgiven continuously; alternatively, in some embodiments, the dose of drugbeing administered is temporarily reduced or temporarily suspended for acertain length of time (i.e., a “drug holiday”). The length of the drugholiday can vary between 2 days and 1 year, including by way of exampleonly, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days,15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320days, 350 days, or 365 days. In some embodiments, the dose reductionduring a drug holiday is from about 10% to about 100%, including, by wayof example only, about 10%, about 15%, about 20%, about 25%, about 30%,about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%,or about 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, can be reduced, as a function ofthe symptoms, to a level at which the improved disease, disorder orcondition is retained. Patients can, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

In some embodiments, the pharmaceutical composition described herein isin unit dosage forms suitable for single administration of precisedosages. In unit dosage form, the formulation is divided into unit dosescontaining appropriate quantities of one or more compound. In someembodiments, the unit dosage is in the form of a package containingdiscrete quantities of the formulation. Non-limiting examples arepackaged tablets or capsules, and powders in vials or ampoules. In someembodiments, aqueous suspension compositions are packaged in single-dosenon-reclosable containers. Alternatively, in some embodiments,multiple-dose reclosable containers are used, in which case it istypical to include a preservative in the composition. By way of exampleonly, in some embodiments, formulations for parenteral injection arepresented in unit dosage form, which include, but are not limited toampoules, or in multi-dose containers, with an added preservative.

Toxicity and therapeutic efficacy of such therapeutic regimens can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (thedose therapeutically effective in 50% of the population). The dose ratiobetween the toxic and therapeutic effects is the therapeutic index andit can be expressed as the ratio between LD₅₀ and ED₅₀. Compoundsexhibiting high therapeutic indices are preferred. The data obtainedfrom cell culture assays and animal studies can be used in formulating arange of dosage for use in human. The dosage of such compounds liespreferably within a range of circulating concentrations that include theED₅₀ with minimal toxicity. The dosage may vary within this rangedepending upon the dosage form employed and the route of administrationutilized.

Preparation of the Compounds of the Invention

The following Reaction Schemes illustrate methods to make compounds ofthis invention, i.e., compounds of formula (I):

where n, A, B, E, R¹ and R² are as defined above in the Summary of theInvention, as an individual stereoisomer, enantiomer or tautomer thereofor a mixture thereof; or a pharmaceutically acceptable salt, solvate, orprodrug thereof.

It is understood that one skilled in the art would be able to make thecompounds described herein by similar methods or by methods known to oneskilled in the art. It is also understood that one skilled in the artwould be able to make in a similar manner as described below othercompounds described herein not specifically illustrated below by usingthe appropriate starting components and modifying the parameters of thesynthesis as needed. In general, starting components may be obtainedfrom sources such as Sigma Aldrich, Lancaster Synthesis, Inc.,Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. orsynthesized according to sources known to those skilled in the art (see,e.g., Smith, M. B. and J. March, March's Advanced Organic Chemistry:Reactions, Mechanisms, and Structure, 6th edition (Wiley, 2007)) orprepared as described herein.

It is also understood that in the following description, combinations ofsubstituents and/or variables of the depicted formulae are permissibleonly if such contributions result in stable compounds.

It will also be appreciated by those skilled in the art that in theprocess described below the functional groups of intermediate compoundsmay need to be protected by suitable protecting groups. Such functionalgroups include hydroxy, amino, mercapto and carboxylic acid. Suitableprotecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl(e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl),tetrahydropyranyl, benzyl, and the like. Suitable protecting groups foramino, amidino and guanidino include t-butoxycarbonyl,benzyloxycarbonyl, and the like. Suitable protecting groups for mercaptoinclude —C(O)—R″ (where R″ is alkyl, aryl or aralkyl), p-methoxybenzyl,trityl and the like. Suitable protecting groups for carboxylic acidinclude alkyl, aryl or arylalkyl esters.

In some embodiments, protecting groups are added or removed inaccordance with standard techniques, which are known to one skilled inthe art and as described herein.

The use of protecting groups is described in detail in Greene, T. W. andP. G. M. Wuts, Greene's Protective Groups in Organic Synthesis (2006),4^(th) Ed., Wiley. The protecting group may also be a polymer resin suchas a Wang resin or a 2-chlorotrityl-chloride resin.

It will also be appreciated by those skilled in the art, although suchprotected derivatives of compounds of this invention may not possesspharmacological activity as such, they may be administered to a mammaland thereafter metabolized in the body to form compounds describedherein which are pharmacologically active. Such derivatives maytherefore be described as “prodrugs”. All prodrugs of compounds of thisinvention are included within the scope of the compounds describedherein.

The compounds of formula (I), (II), (III), or (IV) may contain at leastone asymmetric carbon atom and thus can exist as racemates, enantiomersand/or diastereoisomers. In some embodiments, specific enantiomers ordiastereoisomers are prepared by utilizing the appropriate chiralstarting material. Alternatively, in some embodiments, diastereoisomericmixtures or racemic mixtures of compounds of formula (I), (II), (III),or (IV) are resolved into their respective enantiomers ordiastereoisomers. Methods for resolution of diastereoisomeric mixturesor racemic mixtures of the compounds of formula (I), (II), (III), or(IV), as described herein, or intermediates prepared herein, are wellknown in the art (e.g., E. L. Eliel and S. H. Wilen, in Stereochemistryof Organic Compounds; John Wiley & Sons: New York, 1994; Chapter 7, andreferences cited therein). Suitable processes such as crystallization(e.g., preferential crystallization, preferential crystallization in thepresence of additives), asymmetric transformation of racemates, chemicalseparation (e.g., formation and separation of diastereomers such asdiastereomeric salt mixtures or the use of other resolving agents;separation via complexes and inclusion compounds), kinetic resolution(e.g., with titanium tartrate catalyst), enzymatic resolution (e.g.,lipase mediated) and chromatographic separation (e.g., HPLC with chiralstationary phase and/or with simulated moving bed technology, orsupercritical fluid chromatography and related techniques) are some ofthe examples that may be applied (see e.g., T. J. Ward, AnalyticalChemistry, 2002, 2863-2872).

Preparation of Compounds of Formula (I-1)

Compounds of formula (I-1) are compounds of formula (I) and are preparedas set forth below in Reaction Scheme 1 wherein n, E, A, B, R² and R⁵are as described above in the Summary of the Invention:

Compounds of formula (A) and formula (C) are commercially available ormay be prepared by methods known to one skilled in the art.

In general, compounds of formula (I-1) are prepared by first reducing acompound of formula (A) in a protic solvent, such as methanol, understandard reduction conditions, such as treatment with Raney-Nickel atroom temperature. The compound of formula (B) is then isolated from thereaction mixture by standard techniques, such as evaporation andpurification by flash column chromatography. The compound of formula (B)is then treated with a compound of formula (C) at room temperature understandard amide formation conditions to yield a compound of formula(I-1), which is isolated from the reaction conditions by standardisolation techniques, such as organic solvent extraction, evaporationand column chromatography.

Preparation of Compounds of Formula (I-2)

Compounds of formula (I-2) are compounds of formula (I) and are preparedas set forth below in Reaction Scheme 2 wherein E, A, B and R⁵ are asdescribed above in the Summary of the Invention and each X isindependently bromo or chloro and R⁹ is alkylene:

Compounds of formula (C), formula (D) and formula (E) are commerciallyavailable or may be prepared by methods known to one skilled in the art.In particular, compounds of formula (E) are optionally substitutedN-heterocyclics as defined herein.

In general, compounds of formula (I-2) are prepared by first treating acompound of formula (D) under standard alkylation conditions to yield acompounds of formula (F), which is isolated from the reaction mixture bystandard isolation techniques, such as evaporation and columnchromatography. The compound of formula (F) is then treated understandard Buchwald-Hartwig amination reaction via the palladium-catalyzedcross-coupling of amines with aryl halides conditions to yield acompound of formula (G), which is isolated by standard isolationtechniques, such as evaporation and column chromatography. The compoundof formula (G) is then treated with a compound of formula (C) understandard amide formation conditions to yield a compound of formula(I-2), which is isolated from the reaction conditions by standardisolation techniques, such as organic extraction, evaporation and columnchromatography.

Preparation of Compounds of Formula (I-3)

Compounds of formula (I-3) are compounds of formula (I) and are preparedas set forth below in Reaction Scheme 3 wherein E, A, R^(4a), R^(4b),R^(4c), R^(4d) and R⁵ are as described above in the Summary of theInvention and each X is independently bromo or chloro, R¹⁰ is alkyl andPG is a nitrogen protecting group, such as t-butoxycarbonyl:

Compounds of formula (G), formula (H) and formula (C) are commerciallyavailable or may be prepared by methods known to one skilled in the art.

In general, compounds of formula (I-3) are prepared by first treating acompound of formula (G) with a compound of formula (H) under standardnucleophilic substitution under basic conditions to yield a compound offormula (J), which is isolated from the reaction mixture by standardisolation techniques, such as organic solvent extraction, evaporationand column chromatography. The compound of formula (J) is then treatedwith under standard lactam cyclization conditions to yield a compound offormula (K), which is isolated from the reaction mixture by standardisolation techniques, such as solvent extraction, evaporation and columnchromatography. The compound of formula (K) is then treated with acompound of formula (C) under standard amide formation conditions toyield a compound of formula (I-2), which is isolated from the reactionconditions by standard isolation techniques, such as organic extraction,evaporation and column chromatography.

Preparation of Compounds of Formula (I-4)

Compounds of formula (I-4) are compounds of formula (I) and are preparedas set forth below in Reaction Scheme 4 wherein E, A and R⁵ are asdescribed above in the Summary of the Invention and X is independentlybromo or chloro and R¹⁰ is alkyl:

Compounds of formula (G), formula (L) and formula (C) are commerciallyavailable or may be prepared by methods known to one skilled in the art.

In general, compounds of formula (I-4) are prepared by first treating acompound of formula (G) with a compound of formula (L) under standardalkylation conditions to yield a compound of formula (M), which isisolated from the reaction mixture by standard isolation techniques,such as filtration. The compound of formula (M) is then treated withunder standard lactam cyclization conditions to yield a compound offormula (N), which is isolated from the reaction mixture by standardisolation techniques, such as evaporation and column chromatography. Thecompound of formula (N) is then treated with a compound of formula (C)under standard amide formation conditions to yield a compound of formula(I-4), which is isolated from the reaction conditions by standardisolation techniques, such as organic extraction, evaporation and columnchromatography.

Preparation of Compounds of Formula (I-5)

Compounds of formula (I-5) are compounds of formula (I) and are preparedas set forth below in Reaction Scheme 5 wherein E, A and R⁵ are asdescribed above in the Summary of the Invention and X is independentlybromo or chloro and R¹⁰ is alkyl:

Compounds of formula (O), formula (P) and formula (C) are commerciallyavailable or may be prepared by methods known to one skilled in the art.

In general, compounds of formula (I-5) are prepared by first treating acompound of formula (O) with a compound of formula (P) under standardnucleophilic substitution under basic conditions to yield a compound offormula (Q), which is isolated from the reaction mixture by standardisolation techniques, such as extraction, evaporation and columnchromatography. The compound of formula (Q) is then treated underFischer indole-like synthesis conditions to yield a compound of formula(R), which is isolated from the reaction mixture by standard isolationtechniques, such as such as extraction, evaporation and columnchromatography. The compound of formula (R) is then treated understandard reduction conditions, such as treatment with Raney-Nickel andhydrazine hydrate, to yield a compound of formula (S), which is isolatedfrom the reaction mixture by standard isolation techniques, such as suchas evaporation and column chromatography. The compound of formula (S) isthen treated with a compound of formula (C) under standard amideformation conditions to yield a compound of formula (I-5), which isisolated from the reaction conditions by standard isolation techniques,such as organic extraction, evaporation and column chromatography.

Preparation of Compounds of Formula (I-6)

Compounds of formula (I-6) are compounds of formula (I) and are preparedas set forth below in Reaction Scheme 6 wherein E, A and R⁵ are asdescribed above in the Summary of the Invention and R¹⁰ is alkyl:

Compounds of formula (T), formula (U) and formula (C) are commerciallyavailable or may be prepared by methods known to one skilled in the art.

In general, compounds of formula (I-6) are prepared by first treating acompound of formula (T) with a compound of formula (U) under standardreductive amination reaction conditions to form a compound of formula(V), which is isolated from the reaction conditions by standardisolation techniques, such as organic solvent extraction andevaporation. The compound of formula (V) is then treated under standardFischer indole synthesis conditions to form a compound of formula (W),which is isolated from the reaction conditions by standard isolationtechniques, such as organic solvent extraction, evaporation and columnchromatography. The compound of formula (W) is then treated understandard reduction conditions, such as treatment with Raney-Nickel andhydrazine hydrate at room temperature, to form a compound of formula(X), which is isolated from the reaction conditions by standardisolation techniques, such as filtration, evaporation and flash columnchromatography. The compound of formula (X) is then treated with acompound of formula (C) under standard amide formation conditions toyield a compound of formula (I-6), which is isolated from the reactionconditions by standard isolation techniques, such as organic solventextraction, evaporation and column chromatography.

Preparation of Compounds of Formula (I-7)

Compounds of formula (I-7) are compounds of formula (I) and are preparedas set forth below in Reaction Scheme 7 wherein n, E, A, B and R² are asdescribed above in the Summary of the Invention and X is bromo orchloro, R⁹ is alkylene, R^(7b) is halo, haloalkyl, —CN, —NO₂, —N(R⁶)₂,—N(R⁶)C(O)OR⁶, —C(O)R⁶, —C(O)OR⁶ or —C(O)N(R⁶)₂ where R⁶ is as describedabove in the Summary of the Invention and

is a monocyclic N-heteroaryl:

Compounds of formula (Y), formula (Z) and formula (CC) are commerciallyavailable or may be prepared by methods known to one skilled in the art.

In general, compounds of formula (I-7) are prepared by first treating acompound of formula (Y) with a compound of formula (Z) under standardnitrogen alkylation conditions to form a compound of formula (AA), whichis isolated from the reaction conditions by standard isolationtechniques, such as organic solvent extraction and columnchromatography. The compound of formula (AA) is then treated understandard reduction conditions, such as treatment with iron in aceticacid, to form a compound of formula (BB), which is isolated from thereaction conditions by standard isolation techniques, such as organicsolvent extraction and evaporation. The compound of formula (BB) is thentreated with a compound of formula (CC) under standard amide formationconditions to yield a compound of formula (I-7), which is isolated fromthe reaction conditions by standard isolation techniques, such asorganic solvent extraction, evaporation and column chromatography.

Preparation of Compounds of Formula (I-87)

Compounds of formula (I-8) are compounds of formula (I) and are preparedas set forth below in Reaction Scheme 8 wherein n, E, A, B and R² are asdescribed above in the Summary of the Invention and X is bromo orchloro, R⁹ is alkylene, R¹⁰ is alkyl, R^(5a) is halo, haloalkyl, —CN,—NO₂, —N(R⁶)₂, —N(R⁶)C(O)OR⁶, —C(O)R⁶, —C(O)OR⁶ or —C(O)N(R⁶)₂ where R⁶is as described above in the Summary of the Invention and

is an optionally substituted N-heteroaryl:

Compounds of formula (DD), formula (EE) and formula (B) are commerciallyavailable or may be prepared by methods known to one skilled in the art.

In general, compounds of formula (I-8) are prepared by first treating acompound of formula (DD) with a compound of formula (EE) under standardnitrogen alkylation conditions to form a compound of formula (FF), whichis isolated from the reaction conditions by standard isolationtechniques, such as organic solvent extraction, evaporation and columnchromatography. The compound of formula (FF) is then treated understandard basic hydrolysis conditions to form a compound of formula (GG),which is isolated from the reaction conditions by standard isolationtechniques, such as organic solvent extraction and evaporation ofsolvents. The compound of formula (GG) is then treated with a compoundof formula (B) under standard amide formation conditions to yield acompound of formula (I-8), which is isolated from the reactionconditions by standard isolation techniques, such as organic solventextraction, evaporation and column chromatography.

SYNTHETIC EXAMPLES

The following Synthetic Examples, which are directed to the preparationof the intermediates and/or compounds described herein, are provided asa guide to assist in the practice of the invention, and are not intendedas a limitation on the scope of the invention.

ABBREVIATIONS

The following abbreviations may be used herein in the followingSynthetic Examples:

-   AcOH for acetic acid;-   ACN for acetonitrile;-   Boc for t-butoxycarbonyl;-   BH₃.THF for borane tetrahydrofuran complex;-   BOP for benzotriazol-1-yloxy)tris(dimethylamino)phosphonium    hexafluorophosphate;-   18-crown-6 for 1,4,7,10,13,16-hexaoxacyclooctadecane;-   DCM for dichloromethane;-   DMF for N,N-dimethylformamide;-   Et₃N for triethylamine;-   EtOAc for ethyl acetate;-   EtOH for ethanol;-   h for hours;-   HATU for    1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium    3-oxide hexafluorophosphate;-   HBTU for O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate;-   LiHMDS for lithium bis(trimethylsilyl)amide;-   min. for minutes;-   MeOH for methanol;-   NaOH for sodium hydroxide;-   NMR for nuclear magnetic resonance;-   Pd/C for palladium metal on charcoal;-   Pd₂(dba)₃ for Tris(dibenzylideneacetone)dipalladium(0);-   Ph for phenyl;-   P^(t)Bu₃ for tri-tert-butylphosphine;-   PPA for polyphosphoric acid-   ^(i)Pr₂NEt for diisopropylethylamine;-   Ra-Ni for Raney-Nickel;-   rt for room temperature;-   TBAF for tetrabutylammonium fluoride;-   TFA for trifluoroacetic acid;-   THF for tetrahydrofuran;-   TLC for thin layer chromatography.

Synthetic Example 1 Synthesis of1-Benzyl-N-(3-(morpholinomethyl)-1H-indol-5-yl)-1H-pyrazole-4-carboxamide,Compound #1

A. A solution of 4-((5-nitro-1H-indol-3-yl)methyl)morpholine (compound(1A) (0.42 g, 1.607 mmol) in MeOH (20 mL) was treated with Raney-Nickel(˜100 mg) followed by hydrazine hydrate (0.78 mL, 16.074 mmol) at roomtemperature. The reaction was refluxed for 10-15 minutes in a pre-heatedoil bath and then brought back to room temperature. The solution wasfiltered through a pad of celite and washed with methanol (2×15 mL). Thecombined methanol layer was evaporated and crude was purified by flashcolumn chromatography (2M NH₃ in MeOH: CH₂Cl₂, 5:95) on silica gel toobtain 3-(morpholinomethyl)-1H-indol-5-amine, compound 1b, (0.3 g, 81%)as a brown solid.

B. A solution of 3-(morpholinomethyl)-1H-indol-5-amine (compound 1b,0.215 g, 0.929 mmol), 1-benzyl-1H-pyrazole-4-carboxylic acid (compound1c, 0.21 g, 1.022 mmol) and Et₃N (0.26 mL, 1.859 mmol) in dry DMF (10mL) was treated with HBTU (0.35 g, 0.929 mmol) at room temperature andstirred for 4 hours. The reaction was diluted with 1N NaOH solution (50mL), water (50 mL) and product was extracted into ethyl acetate (2×50mL). The combined ethyl acetate layer was washed with brine (50 mL) anddried (Na₂SO₄). Solvent was evaporated and crude was purified by columnchromatography (2M NH₃ in MeOH: CH₂Cl₂, 2:98 to 5:95) on silica gel toobtain1-benzyl-N-(3-(morpholinomethyl)-1H-indol-5-yl)-1H-pyrazole-4-carboxamide,compound #1, (0.3 g, 78%) as an off-white solid. ¹H NMR (DMSO-d₆) δ 2.36(brs, 4H), 3.50-3.60 (m, 6H), 5.39 (s, 2H), 7.21 (s, 1H), 7.27-7.39 (m,7H), 7.87 (s, 1H), 8.06 (s, 1H), 8.41 (s, 1H), 9.70 (s, 1H), 10.88 (s,1H); ESI-MS (m/z, %): 416 (MH⁺, 100%).

Synthetic Example 2 Synthesis of1-Benzyl-N-(3-(morpholinomethyl)-1H-indol-6-yl)-1H-pyrazole-4-carboxamide,Compound #2

A. A solution of 4-((6-nitro-1H-indol-3-yl)methyl)morpholine (compound2a, 0.325 g, 1.243 mmol) in MeOH (20 mL) was treated with Raney-Nickel(˜50 mg) followed by hydrazine hydrate (0.6 mL, 12.438 mmol) at roomtemperature. The reaction was refluxed for 10-15 minutes in a pre-heatedoil bath and then brought back to room temperature. The solution wasfiltered through a pad of celite and washed with methanol (2×15 mL). Thecombined methanol layer was evaporated and crude was purified by flashcolumn chromatography (2M NH₃ in MeOH: CH₂Cl₂, 5:95) on silica gel toobtain 3-(morpholinomethyl)-1H-indol-6-amine, compound 2b (0.27 g, 94%)as a tan solid.

B. A solution of 3-(morpholinomethyl)-1H-indol-6-amine (compound 2b,0.26 g, 1.124 mmol), 1-benzyl-1H-pyrazole-4-carboxylic acid (compound1c, 0.25 g, 1.236 mmol) and Et₃N (0.31 mL, 2.248 mmol) in dry DMF (10mL) was treated with HBTU (0.42 g, 1.124 mmol) at room temperature andstirred for 4 h. The reaction was diluted with 1N NaOH solution (50 mL),water (50 mL) and product was extracted into ethyl acetate (2×50 mL).The combined ethyl acetate layer was washed with brine (50 mL) and dried(Na₂SO₄). Solvent was evaporated and crude was purified by columnchromatography (2M NH₃ in MeOH: CH₂Cl₂, 2:98 to 5:95) on silica gel toobtain1-benzyl-N-(3-(morpholinomethyl)-1H-indol-6-yl)-1H-pyrazole-4-carboxamide,compound #2, (0.43 g, 92%) as an off-white solid. ¹H NMR (DMSO-d₆) δ2.36 (brs, 4H), 3.54-3.57 (m, 6H), 5.39 (s, 2H), 7.16-7.18 (m, 2H),7.28-7.38 (m, 5H), 7.54 (d, 1H, J=4.2 Hz), 7.94 (s, 1H), 8.06 (s, 1H),8.43 (s, 1H), 9.72 (s, 1H), 10.87 (s, 1H); ESI-MS (m/z, %): 416 (MH⁺,100%).

Synthetic Example 3 Synthesis of1-Benzyl-N-(3-((4-methylpiperazin-1-yl)methyl)-1H-indol-5-yl)-1H-pyrazole-4-carboxamide,Compound #3

A. A solution of 3-((4-methylpiperazin-1-yl)methyl)-5-nitro-1H-indole(compound 3a, 0.25 g, 0.911 mmol) in MeOH (10 mL) was treated withRaney-Nickel (˜50 mg) followed by hydrazine hydrate (0.44 mL, 9.113mmol) at room temperature. The reaction was refluxed for 10-15 minutesin a pre-heated oil bath and then brought back to room temperature. Thesolution was filtered through a pad of celite and washed with methanol(2×15 mL). The combined methanol layer was evaporated and crude waspurified by flash column chromatography (2M NH₃ in MeOH: CH₂Cl₂, 5:95)on silica gel to obtain3-((4-methylpiperazin-1-yl)methyl)-1H-indol-5-amine, compound 3b, (0.19g, 86%) as a tan solid.

B. A solution of 3-((4-methylpiperazin-1-yl)methyl)-1H-indol-5-amine(compound 3b, 0.175 g, 0.716 mmol), 1-benzyl-1H-pyrazole-4-carboxylicacid (compound 1c, 0.16 g, 0.787 mmol) and Et₃N (0.2 mL, 1.432 mmol) indry DMF (5 mL) was treated with HBTU (0.27 g, 0.716 mmol) at roomtemperature and stirred for 4 h. The reaction was diluted with 1N NaOHsolution (50 mL), water (50 mL) and product was extracted into ethylacetate (2×50 mL). The combined ethyl acetate layer was washed withbrine (50 mL) and dried (Na₂SO₄). Solvent was evaporated and crude waspurified by column chromatography (2M NH₃ in MeOH: CH₂Cl₂, 2:98 to 5:95)on silica gel to obtain1-benzyl-N-(3-((4-methylpiperazin-1-yl)methyl)-1H-indol-5-yl)-1H-pyrazole-4-carboxamide,compound #3, (0.26 g, 85%) as a pale yellow solid. ¹H NMR (DMSO-d₆) δ2.21 (s, 3H), 2.25-2.40 (m, 8H), 3.55 (s, 2H), 5.39 (s, 2H), 7.19 (d,1H, J=1.2 Hz), 7.27-7.39 (m, 7H), 7.83 (s, 1H), 8.06 (s, 1H), 8.41 (s,1H), 9.69 (s, 1H), 10.85 (s, 1H); ESI-MS (m/z, %): 429 (MH⁺, 100%).

Synthetic Example 4 Synthesis of1-Benzyl-N-(3-((4-methylpiperazin-1-yl)methyl)-1H-indol-6-yl)-1H-pyrazole-4-carboxamide,Compound #4

A. A solution of 3-((4-methylpiperazin-1-yl)methyl)-6-nitro-1H-indole(compound 4a, 0.32 g, 1.166 mmol) in MeOH (10 mL) was treated withRaney-Nickel (˜50 mg) followed by hydrazine hydrate (0.56 mL, 11.665mmol) at room temperature. The reaction was refluxed for 10-15 minutesin a pre-heated oil bath and then brought back to room temperature. Thesolution was filtered through a pad of celite and washed with methanol(2×15 mL). The combined methanol layer was evaporated and crude waspurified by flash column chromatography (2M NH₃ in MeOH: CH₂Cl₂, 5:95)on silica gel to obtain3-((4-methylpiperazin-1-yl)methyl)-1H-indol-6-amine, compound 4b, (0.26g, 91%) as a tan solid.

B. A solution of 3-((4-methylpiperazin-1-yl)methyl)-1H-indol-6-amine(compound 4b, 0.245 g, 1.002 mmol), 1-benzyl-1H-pyrazole-4-carboxylicacid (compound 1c, 0.22 g, 1.102 mmol) and Et₃N (0.28 mL, 2.005 mmol) indry DMF (5 mL) was treated with HBTU (0.38 g, 1.002 mmol) at roomtemperature and stirred for 4 hours. The reaction was diluted with 1NNaOH solution (50 mL), water (50 mL) and product was extracted intoethyl acetate (2×50 mL). The combined ethyl acetate layer was washedwith brine (50 mL) and dried (Na₂SO₄). Solvent was evaporated and crudewas purified by column chromatography (2M NH₃ in MeOH:CH₂Cl₂, 2:98 to5:95) on silica gel to obtain1-benzyl-N-(3-((4-methylpiperazin-1-yl)methyl)-1H-indol-6-yl)-1H-pyrazole-4-carboxamide,compound #4, (0.335 g, 80%) as a pale yellow solid. ¹H NMR (DMSO-d₆) δ2.12 (s, 3H), 2.20-2.40 (m, 8H), 3.56 (s, 2H), 5.39 (s, 2H), 7.14 (d,1H, J=1.2 Hz), 7.16 (dd, 1H, J=0.9, 4.2 Hz), 7.28-7.33 (m, 3H),7.36-7.38 (m, 2H), 7.52 (d, 1H, H=4.2 Hz), 7.93 (s, 1H), 8.06 (s, 1H),8.43 (s, 1H), 9.72 (s, 1H), 10.85 (s, 1H); ESI-MS (m/z, %): 429 (MH⁺,100%).

Synthetic Example 5 Synthesis of1-Benzyl-N-(3-(morpholinomethyl)benzo[b]thiophen-5-yl)-1H-pyrazole-4-carboxamide,Compound #5

A. A solution of 5-bromo-3-(bromomethyl)benzo[b]thiophene (compound 5a,prepared according to the procedure disclosed in PCT Published PatentApplication No. WO 1998/15545, 0.5 g, 1.63 mmol) in acetonitrile (20 mL)was treated with K₂CO₃ (0.67 g, 4.90 mmol), followed by morpholine(compound 5b, 0.28 mL, 3.26 mmol) at room temperature and the resultingsuspension was refluxed for 1 hour. The reaction was brought to roomtemperature, the solid was filtered off and washed with CH₂Cl₂ (15 mL),followed by a 20% methanol in CH₂Cl₂ (2×25 mL). The combined solvent wasevaporated and crude was purified by column chromatography (2M NH₃ inMeOH: CH₂Cl₂, 2:98 to 5:95) on silica gel to obtain4-((5-bromobenzo[b]thiophen-3-yl)methyl)morpholine, compound 5c, (0.48g, 94%) as a yellow oil. ¹H NMR (CDCl₃) δ 2.35-2.60 (m, 4H), 3.60-3.80(m, 6H), 7.31 (brs, 1H), 7.42 (d, 1H, J=4.5 Hz), 7.68 (d, 1H, J=4.2 Hz),8.12 (s, 1H).

B. A solution of 4-((5-bromobenzo[b]thiophen-3-yl)methyl)morpholine(compound 5c, 0.46 g, 1.473 mmol) in dry THF (10 mL) was treated withPd₂(dba)₃ (0.042 g, 0.073 mmol), LiHMDS (2.95 mL, 2.946 mmol, 1Msolution in THF), followed by P^(t)Bu₃ (0.87 mL, 0.294 mmol, 10% inhexanes) at room temperature. The resulting solution was heated at 100°C. in a sealed tube for 2 hours. The reaction was brought to roomtemperature, quenched with 2N HCl solution (10 mL) and stirred for 10minutes. The reaction was basified with 4N NaOH solution and product wasextracted into ethyl acetate (2×50 mL). The combined ethyl acetate layerwas washed with brine (25 mL) and dried (Na₂SO₄). Solvent was evaporatedand crude was purified by column chromatography (2M NH₃ in MeOH: CH₂Cl₂,2.5:97.5 to 5:95) on silica gel to obtain3-(morpholinomethyl)benzo[b]thiophen-5-amine, compound 5d, (0.35 g, 96%)as a light brown solid.

C. A solution of 3-(morpholinomethyl)benzo[b]thiophen-5-amine (compound5d, 0.34 g, 1.369 mmol), 1-benzyl-1H-pyrazole-4-carboxylic acid(compound 1c, 0.3 g, 1.505 mmol) and Et₃N (0.38 mL, 2.738 mmol) in dryDMF (5 mL) was treated with HBTU (0.52 g, 1.369 mmol) at roomtemperature and stirred for 4 hours. The reaction was diluted with 1NNaOH solution (50 mL), water (50 mL) and product was extracted intoethyl acetate (2×50 mL). The combined ethyl acetate layer was washedwith brine (50 mL) and dried (Na₂SO₄). Solvent was evaporated and crudewas purified by column chromatography (2M NH₃ in MeOH: CH₂Cl₂, 2:98 to5:95) on silica gel to obtain1-benzyl-N-(3-(morpholinomethyl)benzo[b]thiophen-5-yl)-1H-pyrazole-4-carboxamide,compound #5, (0.45 g, 76%) as a cream-coloured solid. ¹H NMR (DMSO-d₆) δ2.35-2.45 (m, 4H), 3.52-3.60 (m, 4H), 3.66 (s, 2H), 5.40 (s, 2H),7.29-7.33 (m, 3H), 7.36-7.39 (m, 2H), 7.58 (s, 1H), 7.68 (dd, 1H, J=1.2,4.3 Hz), 7.89 (d, 1H, J=4.5 Hz), 8.09 (s, 1H), 8.31 (d, 1H, J=0.9 Hz),8.47 (s, 1H), 9.97 (s, 1H).

Synthetic Example 6 Synthesis of1-Benzyl-N-(3-(piperazin-1-ylmethyl)benzo[b]thiophen-5-yl)-1H-pyrazole-4-carboxamide,Compound #6

A. A solution of 5-bromo-3-(bromomethyl)benzo[b]thiophene (compound 5a,prepared according to the procedure disclosed in PCT Published PatentApplication No. WO 1998/15545, 0.5 g, 1.63 mmol) in acetonitrile (20 mL)was treated with K₂CO₃ (0.67 g, 4.90 mmol), followed by tert-butylpiperazine-1-carboxylate (compound 6a, 0.34 g, 1.79 mmol) at roomtemperature and the resulting suspension was refluxed for 1 hour. Thereaction was brought to room temperature, solid was filtered off andwashed with CH₂Cl₂ (15 mL), followed by a 20% methanol in CH₂Cl₂ (2×25mL). The combined solvent was evaporated and crude was purified bycolumn chromatography (2M NH₃ in MeOH: CH₂Cl₂, 2:98 to 5:95) on silicagel to obtain tert-butyl4-((5-bromobenzo[b]thiophen-3-yl)methyl)piperazine-1-carboxylate,compound 6b, (0.78 g, 89%) as a pale yellow solid. ¹H NMR (CDCl₃) δ 1.43(s, 9H), 2.35-2.48 (m, 4H), 3.40-3.50 (m, 4H), 3.69 (brs, 2H), 7.28-7.36(m, 1H), 7.42 (d, 1H, J=4.2 Hz), 7.68 (d, 1H, J=4.2 Hz), 8.10 (s, 1H).

B. A solution of Pd₂(dba)₃ (0.053 g, 0.093 mmol) in dry THF (5 mL) wastreated with P^(t)Bu₃ (1.11 mL, 0.374 mmol, 10% in hexanes) at roomtemperature. After stirring for 5 minutes, the reaction was treated witha solution of tert-butyl4-((5-bromobenzo[b]thiophen-3-yl)methyl)piperazine-1-carboxylate(compound 6b, 0.77 g, 1.871 mmol) in dry THF (10 mL) followed by LiHMDS(3.74 mL, 3.74 mmol, 1M solution in THF). The resulting solution washeated at 100° C. in a sealed tube for 2 hours. The reaction was broughtto room temperature, quenched with TBAF (10 mL, 1M in THF) and stirredfor 10 minutes. The reaction was basified with 4N NaOH solution andproduct was extracted into ethyl acetate (2×50 mL). The combined ethylacetate layer was washed with brine (25 mL) and dried (Na₂SO₄). Solventwas evaporated and crude was purified by column chromatography (2M NH₃in MeOH: CH₂Cl₂, 2.5:97.5 to 5:95) on silica gel to obtain tert-butyl4-((5-aminobenzo[b]thiophen-3-yl)methyl)piperazine-1-carboxylate,compound 6c, (0.655 g, quantitative) as a light brown foam.

C. A solution of tert-butyl4-((5-aminobenzo[b]thiophen-3-yl)methyl)piperazine-1-carboxylate(compound 6c, 0.65 g, 2.057 mmol), 1-benzyl-1H-pyrazole-4-carboxylicacid (compound 1c, 0.42 g, 1.87 mmol) and Et₃N (0.52 mL, 3.741 mmol) indry DMF (10 mL) was treated with HBTU (0.71 g, 1.87 mmol) at roomtemperature and stirred for 4 h. The reaction was diluted with 1N NaOHsolution (50 mL), water (50 mL) and product was extracted into ethylacetate (2×50 mL). The combined ethyl acetate layer was washed withbrine (50 mL) and dried (Na₂SO₄). Solvent was evaporated and crude waspurified by column chromatography (2M NH₃ in MeOH: CH₂Cl₂, 2:98 to 5:95)on silica gel to obtain tert-butyl4-((5-(1-benzyl-1H-pyrazole-4-carboxamido)benzo[b]thiophen-3-yl)methyl)piperazine-1-carboxylate,compound 6d (0.85 g, 86%) as a yellow solid. ¹H NMR (DMSO-d₆) δ 1.38 (s,9H), 2.35-2.45 (m, 4H), 3.32-3.40 (m, 4H), 3.68 (s, 2H), 5.40 (s, 2H),7.29-7.33 (m, 3H), 7.36-7.39 (m, 2H), 7.57 (s, 1H), 7.68 (dd, 1H, J=1.2,4.3 Hz), 7.89 (d, 1H, J=4.2 Hz), 8.09 (s, 1H), 8.32 (d, 1H, J=0.9 Hz),8.46 (s, 1H), 9.99 (s, 1H).

D. A suspension of tert-butyl4-((5-(1-benzyl-1H-pyrazole-4-carboxamido)benzo[b]thiophen-3-yl)methyl)piperazine-1-carboxylate(compound 6d, 0.82 g, 1.542 mmol) in dry CH₂Cl₂ (12 mL) was treated withTFA (8 mL) at 0° C. The reaction was brought to room temperature andstirred for additional 2 hours. Solvent was evaporated and crude wasbasified with 2N NaOH solution and product was extracted into ethylacetate (2×25 mL). The combined ethyl acetate layer was washed withbrine (25 mL) and dried (Na₂SO₄). Solvent was evaporated and crude waspurified by column chromatography (2M NH₃ in MeOH:CH₂Cl₂, 1:9) on silicagel to obtain1-benzyl-N-(3-(piperazin-1-ylmethyl)benzo[b]thiophen-5-yl)-1H-pyrazole-4-carboxamide,compound #6, (0.5 g, 76%) as a cream colour solid. ¹H NMR (DMSO-d₆) δ2.30-2.40 (m, 4H), 2.66-2.68 (m, 4H), 3.61 (s, 2H), 5.40 (s, 2H),7.29-7.33 (m, 3H), 7.36-7.39 (m, 2H), 7.54 (s, 1H), 7.69 (dd, 1H, J=1.2,4.3 Hz), 7.89 (d, 1H, J=4.2 Hz), 8.09 (s, 1H), 8.30 (d, 1H, J=0.9 Hz),8.47 (s, 1H), 9.96 (s, 1H).

Synthetic Example 7 Synthesis of1-benzyl-N-(3-(morpholinomethyl)benzofuran-6-yl)-1H-pyrazole-4-carboxamide,Compound #7

A. A solution of 6-bromo-3-(bromomethyl)benzofuran (compound 7a,prepared according to the methods disclosed in Bioorg. & Med. Chem.,1997, 5, 445-459, 0.66 g, 2.276 mmol) in acetonitrile (20 mL) wastreated with K₂CO₃ (0.94 g, 6.828 mmol), followed by morpholine(compound 5b, 0.24 mL, 2.731 mmol) at room temperature and the resultingsuspension was refluxed for 1 hour. The reaction was brought to roomtemperature, solid was filtered off and washed with CH₂Cl₂ (15 mL),followed by a 20% methanol in CH₂Cl₂ (2×25 mL). The combined solvent wasevaporated and crude was purified by column chromatography (2M NH₃ inMeOH: CH₂Cl₂, 2:98 to 5:95) on silica gel to obtain4-((6-bromobenzofuran-3-yl)methyl)morpholine, compound 7b, (0.66 g, 98%)as a yellow oil.

B. A solution of Pd₂(dba)₃ (0.045 g, 0.077 mmol) in dry THF (3 mL) wastreated with P^(t)Bu₃ (0.92 mL, 0.310 mmol, 10% in hexanes) at roomtemperature. After stirring for 5 minutes, the reaction was treated witha solution of 4-((6-bromobenzofuran-3-yl)methyl)morpholine (compound 7b,0.46 g, 1.553 mmol) in dry THF (7 mL) followed by LiHMDS (3.1 mL, 3.106mmol, 1M solution in THF). The resulting solution was heated at 100° C.in a sealed tube for 3 hours. The reaction was brought to roomtemperature, quenched with 2N HCl (10 mL) and stirred for 10 minutes.The reaction was basified with 4N NaOH solution and product wasextracted into ethyl acetate (2×50 mL). The combined ethyl acetate layerwas washed with brine (25 mL) and dried (Na₂SO₄). Solvent was evaporatedand crude was purified by column chromatography (2M NH₃ in MeOH: CH₂Cl₂,2.5:97.5 to 5:95) on silica gel to obtain3-(morpholinomethyl)benzofuran-6-amine, compound 7c, (0.35 g, 97%) as abrown oil.

C. A solution of 3-(morpholinomethyl)benzofuran-6-amine (compound 7c.0.34 g, 1.463 mmol), 1-benzyl-1H-pyrazole-4-carboxylic acid (compound1c, 0.33 g, 1.610 mmol) and Et₃N (0.4 mL, 2.927 mmol) in dry DMF (10 mL)was treated with HBTU (0.56 g, 1.463 mmol) at room temperature andstirred for 4 hours. The reaction was diluted with 1N NaOH solution (50mL), water (50 mL) and product was extracted into ethyl acetate (2×50mL). The combined ethyl acetate layer was washed with brine (50 mL) anddried (Na₂SO₄). Solvent was evaporated and crude was purified by columnchromatography (2M NH₃ in MeOH: CH₂Cl₂, 2:98 to 5:95) on silica gel toobtain1-benzyl-N-(3-(morpholinomethyl)benzofuran-6-yl)-1H-pyrazole-4-carboxamide,compound #7, (0.24 g, 40%) as a yellow solid. ¹H NMR (DMSO-d₆) δ2.35-2.45 (m, 4H), 3.52-3.65 (m, 6H), 5.40 (s, 2H), 7.28-7.33 (m, 3H),7.36-7.38 (m, 2H), 7.45 (dd, 1H, 0.9, 4.3 Hz), 7.65 (d, 1H, J=4.2 Hz),7.82 (s, 1H), 8.07 (s, 1H), 8.09 (d, 1H, J=0.9 Hz), 8.45 (s, 1H), 9.96(s, 1H).

Synthetic Example 8 Synthesis of1-benzyl-N-(3-(morpholinomethyl)benzofuran-5-yl)-1H-pyrazole-4-carboxamide,Compound #8

A. A solution of 5-bromo-3-(bromomethyl)benzofuran (compound 8a,prepared according to the methods disclosed in Bioorg. & Med. Chem.,1997, 5, 445-459, 1.0 g, 3.44 mmol) in acetonitrile (20 mL) was treatedwith K₂CO₃ (1.43 g, 10.34 mmol), followed by morpholine (compound 5b,0.36 mL, 4.13 mmol) at room temperature and the resulting suspension wasrefluxed for 1 h. The reaction was brought to room temperature, solidwas filtered off and washed with CH₂Cl₂ (15 mL), followed by a 20%methanol in CH₂Cl₂ (2×25 mL). The combined solvent was evaporated andcrude was purified by column chromatography (2M NH₃ in MeOH: CH₂Cl₂,2:98 to 5:95) on silica gel to obtain4-((5-bromobenzofuran-3-yl)methyl)morpholine, compound 8b, (1.01 g,quantitative) as a pale yellow solid.

B. A solution of Pd₂(dba)₃ (0.097 g, 0.168 mmol) in dry THF (5 mL) wastreated with P^(t)Bu₃ (2.0 mL, 0.675 mmol, 10% in hexanes) at roomtemperature. After stirring for 5 minutes, the reaction was treated witha solution of 4-((5-bromobenzofuran-3-yl)methyl)morpholine (compound 8b,1.0 g, 3.376 mmol) in dry THF (10 mL) followed by LiHMDS (6.75 mL, 6.753mmol, 1M solution in THF). The resulting solution was heated at 100° C.in a sealed tube for 3 h. The reaction was brought to room temperature,quenched with 2N HCl (10 mL) and stirred for 10 min. The reaction wasbasified with 4N NaOH solution and product was extracted into ethylacetate (2×50 mL). The combined ethyl acetate layer was washed withbrine (25 mL) and dried (Na₂SO₄). Solvent was evaporated and crude waspurified by column chromatography (2M NH₃ in MeOH: CH₂Cl₂, 2.5:97.5 to5:95) on silica gel to obtain 3-(morpholinomethyl)benzofuran-5-amine,compound 8c, (0.72 g, 92%) as a brown oil.

C. A solution of 3-(morpholinomethyl)benzofuran-5-amine (0.7 g, 3.013mmol), 1-benzyl-1H-pyrazole-4-carboxylic acid (0.67 g, 3.314 mmol) andEt₃N (0.84 mL, 6.027 mmol) in dry DMF (10 mL) was treated with HBTU(1.14 g, 3.013 mmol) at room temperature and stirred for 4 h. Thereaction was diluted with 1N NaOH solution (50 mL), water (50 mL) andproduct was extracted into ethyl acetate (2×50 mL). The combined ethylacetate layer was washed with brine (50 mL) and dried (Na₂SO₄). Solventwas evaporated and crude was purified by column chromatography (2M NH₃in MeOH: CH₂Cl₂, 2:98 to 5:95) on silica gel to obtain1-benzyl-N-(3-(morpholinomethyl)benzofuran-5-yl)-1H-pyrazole-4-carboxamide,compound #8, (0.54 g, 44%) as an off-white solid. ¹H NMR (DMSO-d₆) δ2.35-2.45 (m, 4H), 3.52-3.65 (m, 6H), 5.40 (s, 2H), 7.28-7.33 (m, 3H),7.36-7.39 (m, 2H), 7.50 (d, 1H, J=4.5 Hz), 7.59 (dd, 1H, 0.9, 4.5 Hz),7.87 (s, 1H), 8.04 (d, 1H, J=1.2 Hz), 8.07 (s, 1H), 8.44 (s, 1H), 9.89(s, 1H).

Synthetic Example 9 Synthesis of1-benzyl-N-(3-(piperazin-1-ylmethyl)benzofuran-5-yl)-1H-pyrazole-4-carboxamide,Compound #9

A. A solution of 5-bromo-3-(bromomethyl)benzofuran (compound 8a,prepared according to the methods disclosed in Bioorg. & Med. Chem.,1997, 5, 445-459, 1.0 g, 3.44 mmol) in acetonitrile (20 mL) was treatedwith K₂CO₃ (1.43 g, 10.34 mmol), followed by tert-butylpiperazine-1-carboxylate (compound 6a, 0.7 g, 3.79 mmol) at roomtemperature and the resulting suspension was refluxed for 1 hour. Thereaction was brought to room temperature, solid was filtered off andwashed with CH₂Cl₂ (15 mL), followed by a 20% methanol in CH₂Cl₂ (2×25mL). The combined solvent was evaporated and crude was purified bycolumn chromatography (2M NH₃ in MeOH: CH₂Cl₂, 2:98 to 5:95) on silicagel to obtain tert-butyl4-((5-bromobenzofuran-3-yl)methyl)piperazine-1-carboxylate, compound 9a,(1.35 g, quantitative) as a pale yellow solid.

B. A solution of Pd₂(dba)₃ (0.073 g, 0.126 mmol) in dry THF (5 mL) wastreated with P^(t)Bu₃ (1.5 mL, 0.505 mmol, 10% in hexanes) at roomtemperature. After stirring for 5 minutes, the reaction was treated witha solution of tert-butyl4-((5-bromobenzofuran-3-yl)methyl)piperazine-1-carboxylate (compound 9a,1.0 g, 2.529 mmol) in dry THF (10 mL) followed by LiHMDS (5.05 mL, 5.059mmol, 1M solution in THF). The resulting solution was heated at 100° C.in a sealed tube for 3 hours. The reaction was brought to roomtemperature, quenched with TBAF (10 mL, 1M in THF) and stirred for 10minutes. The reaction was basified with 4N NaOH solution and product wasextracted into ethyl acetate (2×50 mL). The combined ethyl acetate layerwas washed with brine (25 mL) and dried (Na₂SO₄). Solvent was evaporatedand crude was purified by column chromatography (2M NH₃ in MeOH: CH₂Cl₂,2.5:97.5 to 5:95) on silica gel to obtain tert-butyl4-((5-aminobenzofuran-3-yl)methyl)piperazine-1-carboxylate, compound 9b,(0.8 g, 95%) as a brown solid.

C. A solution of tert-butyl4-((5-aminobenzofuran-3-yl)methyl)piperazine-1-carboxylate (compound 9b,0.75 g, 2.262 mmol), 1-benzyl-1H-pyrazole-4-carboxylic acid (compound1c, 0.5 g, 2.489 mmol) and Et₃N (0.63 mL, 4.525 mmol) in dry DMF (10 mL)was treated with HBTU (0.86 g, 2.262 mmol) at room temperature andstirred for 4 hours. The reaction was diluted with 1N NaOH solution (50mL), water (50 mL) and product was extracted into ethyl acetate (2×50mL). The combined ethyl acetate layer was washed with brine (50 mL) anddried (Na₂SO₄). Solvent was evaporated and crude was purified by columnchromatography (2M NH₃ in MeOH: CH₂Cl₂, 2:98 to 5:95) on silica gel toobtain tert-butyl4-((5-(1-benzyl-1H-pyrazole-4-carboxamido)benzofuran-3-yl)methyl)piperazine-1-carboxylate,compound 9c, (1.13 g, 97%) as a pale yellow solid.

D. A suspension of tert-butyl4-((5-(1-benzyl-1H-pyrazole-4-carboxamido)benzofuran-3-yl)methyl)piperazine-1-carboxylate(compound 9c, 1.0 g, 1.939 mmol) in dry CH₂Cl₂ (12 mL) was treated withTFA (8 mL) at 0° C. The reaction was brought to room temperature andstirred for additional 2 hours. Solvent was evaporated and crude wasbasified with 2N NaOH solution and product was extracted into ethylacetate (2×25 mL). The combined ethyl acetate layer was washed withbrine (25 mL) and dried (Na₂SO₄). Solvent was evaporated and crude waspurified by column chromatography (2M NH₃ in MeOH: CH₂Cl₂, 1:9) onsilica gel to obtain1-benzyl-N-(3-(piperazin-1-ylmethyl)benzofuran-5-yl)-1H-pyrazole-4-carboxamide,compound #9, (0.65 g, 81%) as a pale yellow solid. ¹H NMR (DMSO-d₆) δ2.30-2.40 (m, 4H), 2.66-2.68 (m, 4H), 3.52 (s, 2H), 5.40 (s, 2H),7.28-7.33 (m, 3H), 7.36-7.38 (m, 2H), 7.49 (d, 1H, J=4.5 Hz), 7.59 (dd,1H, J=0.9, 4.5 Hz), 7.85 (s, 1H), 8.03 (s, 1H), 8.07 (s, 1H), 8.45 (s,1H), 9.89 (s, 1H).

Synthetic Example 10 Synthesis of1-benzyl-N-(3-(piperazin-1-ylmethyl)benzofuran-6-yl)-1H-pyrazole-4-carboxamide,Compound #10

A. A solution of 6-bromo-3-(bromomethyl)benzofuran (compound 7a, 0.745g, 2.569 mmol) in acetonitrile (25 mL) was treated with K₂CO₃ (1.06 g,7.708 mmol), followed by tert-butyl piperazine-1-carboxylate (compound6a, 0.53 g, 2.826 mmol) at room temperature and the resulting suspensionwas refluxed for 1 hour. The reaction was brought to room temperature,solid was filtered off and washed with CH₂Cl₂ (15 mL), followed by a 20%methanol in CH₂Cl₂ (2×25 mL). The combined solvent was evaporated andcrude was purified by column chromatography (2M NH₃ in MeOH: CH₂Cl₂,2:98 to 5:95) on silica gel to obtain tert-butyl4-((6-bromobenzofuran-3-yl)methyl)piperazine-1-carboxylate, compound10a, (1.0 g, quantitative) as a pale yellow solid.

B. A solution of Pd₂(dba)₃ (0.070 g, 0.122 mmol) in dry THF (5 mL) wastreated with P^(t)Bu₃ (1.46 mL, 0.49 mmol, 10% in hexanes) at roomtemperature. After stirring for 5 minutes, the reaction was treated witha solution of tert-butyl4-((6-bromobenzofuran-3-yl)methyl)piperazine-1-carboxylate (compound10a, 0.97 g, 2.453 mmol) in dry THF (10 mL) followed by LiHMDS (4.9 mL,4.907 mmol, 1M solution in THF). The resulting solution was heated at100° C. in a sealed tube for 3 hours. The reaction was brought to roomtemperature, quenched with TBAF (10 mL, 1M in THF) and stirred for 10minutes. The reaction was basified with 4N NaOH solution and product wasextracted into ethyl acetate (2×50 mL). The combined ethyl acetate layerwas washed with brine (25 mL) and dried (Na₂SO₄). Solvent was evaporatedand crude was purified by column chromatography (2M NH₃ in MeOH: CH₂Cl₂,2.5:97.5 to 5:95) on silica gel to obtain tert-butyl4-((6-aminobenzofuran-3-yl)methyl)piperazine-1-carboxylate, compound10b, (0.65 g, 80%) as a brown solid.

C. A solution of tert-butyl4-((6-aminobenzofuran-3-yl)methyl)piperazine-1-carboxylate (compound10b, 0.62 g, 1.87 mmol), 1-benzyl-1H-pyrazole-4-carboxylic acid(compound 1c, 0.42 g, 2.05 mmol) and Et₃N (0.52 mL, 3.74 mmol) in dryDMF (10 mL) was treated with HBTU (0.71 g, 1.87 mmol) at roomtemperature and stirred for 4 hours. The reaction was diluted with 1NNaOH solution (50 mL), water (50 mL) and product was extracted intoethyl acetate (2×50 mL). The combined ethyl acetate layer was washedwith brine (50 mL) and dried (Na₂SO₄). Solvent was evaporated and crudewas purified by column chromatography (2M NH₃ in MeOH: CH₂Cl₂, 2:98 to5:95) on silica gel to obtain tert-butyl4-((6-(1-benzyl-1H-pyrazole-4-carboxamido)benzofuran-3-yl)methyl)piperazine-1-carboxylate,compound 10c, (0.44 g, 97%) as a brown solid.

D. A suspension of tert-butyl4-((6-(1-benzyl-1H-pyrazole-4-carboxamido)benzofuran-3-yl)methyl)piperazine-1-carboxylate(compound 10c, 0.35 g, 0.678 mmol) in dry CH₂Cl₂ (12 mL) was treatedwith TFA (8 mL) at 0° C. The reaction was brought to room temperatureand stirred for additional 2 hours. Solvent was evaporated and crude wasbasified with 2N NaOH solution and product was extracted into ethylacetate (2×25 mL). The combined ethyl acetate layer was washed withbrine (25 mL) and dried (Na₂SO₄). Solvent was evaporated and crude waspurified by column chromatography (2M NH₃ in MeOH: CH₂Cl₂, 1:9) onsilica gel to obtain1-benzyl-N-(3-(piperazin-1-ylmethyl)benzofuran-6-yl)-1H-pyrazole-4-carboxamide,compound #10, (0.23 g, 82%) as a pale yellow solid. ¹H NMR (DMSO-d₆) δ2.30-2.40 (m, 4H), 2.66-2.70 (m, 4H), 3.53 (s, 2H), 5.40 (s, 2H),7.28-7.33 (m, 3H), 7.36-7.39 (m, 2H), 7.44 (dd, 1H, J=0.9, 4.2 Hz), 7.64(d, 1H, J=4.5 Hz), 7.80 (s, 1H), 8.07 (2 s, 2H), 8.46 (s, 1H), 9.96 (s,1H).

Synthetic Example 11 Synthesis of(R)-1-benzyl-N-(4-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indol-7-yl)-1H-pyrazole-4-carboxamide,Compound #11

A. A solution of methyl 6-bromo-1H-indole-2-carboxylate (compound 11a,2.0 g, 7.87 mmol) in dry DMF (10 mL) was treated with NaH (0.33 g, 8.65mmol, 60% in mineral oil) at 0° C. and stirred at same temperature for30 more min. The reaction was treated with a solution of tert-butyl(S)-5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (compound11b, 1.87 g, 7.87 mmol) in DMF (10 mL) drop-wise at same temperature.The reaction was brought to room temperature and stirred for 18 hours.The reaction was quenched with the addition of water (100 mL) andproduct was extracted into ethyl acetate (2×100 mL). The combined ethylacetate layer was washed with water (2×50 mL), brine (2×50 mL) and dried(Na₂SO₄). Solvent was evaporated and crude was purified by columnchromatography (EtOAc: Hexanes, 1:9) on silica gel to obtain methyl(R)-6-bromo-1-(1-((tert-butoxycarbonyl)amino)propan-2-yl)-1H-indole-2-carboxylate,compound 11c, (1.7 g, 51%) as an off-white solid.

B. A solution of methyl(R)-6-bromo-1-(1-((tert-butoxycarbonyl)amino)propan-2-yl)-1H-indole-2-carboxylate(compound 11c, 1.7 g, 4.133 mmol) in CH₂Cl₂ (15 mL) was treated with TFA(10 mL) at 0° C. The reaction was brought to room temperature andstirred for 3 hours. Solvent was evaporated and crude was basified with1N NaOH solution (50 mL) and product was extracted into CH₂Cl₂ (3×50mL). The combined CH₂Cl₂ layer was dried (Na₂SO₄), solvent wasevaporated and crude was purified by column chromatography (2M NH₃ inMeOH: CH₂Cl₂, 2.5:97.5) on silica gel to obtain(R)-7-bromo-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one, compound11d, (0.65 g, 57%) as a pale yellow solid. ¹H NMR (DMSO-d₆) δ 1.29 (d,3H, J=3.3 Hz), 3.35-3.38 (m, 1H), 3.82 (dd, 1H, J=2.4, 6.4 Hz),4.88-4.90 (m, 1H), 7.03 (s, 1H), 7.22 (dd, 1H, J=0.9, 3.4 Hz), 7.62 (d,1H, J=4.2 Hz), 7.89 (s, 1H), 8.11 (d, 1H, J=2.4 Hz).

C. A solution of Pd₂(dba)₃ (0.015 g, 0.026 mmol) in dry THF (5 mL) wastreated with P^(t)Bu₃ (0.32 mL, 0.107 mmol, 10% in hexanes) at roomtemperature. After stirring for 5 minutes, the reaction was treated witha solution of(R)-7-bromo-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (compound11d, 0.15 g, 0.537 mmol) in dry THF (5 mL) followed by LiHMDS (1.1 mL,1.074 mmol, 1M solution in THF). The resulting solution was heated at100° C. in a sealed tube for 3 hours. The reaction was brought to roomtemperature, quenched with 2 N HCl solution (10 mL) and stirred for 10minutes. The reaction was basified with 4N NaOH solution and product wasextracted into ethyl acetate (2×50 mL). The combined ethyl acetate layerwas washed with brine (25 mL) and dried (Na₂SO₄). Solvent was evaporatedand crude was purified by column chromatography (2M NH₃ in MeOH: CH₂Cl₂,2.5:97.5 to 5:95) on silica gel to obtain(R)-7-amino-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one, compound11e, (0.06 g, 52%) as a brown solid.

D. A solution of(R)-7-amino-4-methyl-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one (compound11e, 0.06 g, 0.278 mmol), 1-benzyl-1H-pyrazole-4-carboxylic acid(compound 1c, 0.062 g, 0.306 mmol) and Et₃N (0.07 mL, 0.557 mmol) in dryDMF (5 mL) was treated with HBTU (0.105 g, 0.278 mmol) at roomtemperature and stirred for 16 hours. The reaction was diluted with 1NNaOH solution (50 mL), water (50 mL) and product was extracted intoethyl acetate (2×50 mL). The combined ethyl acetate layer was washedwith brine (50 mL) and dried (Na₂SO₄). Solvent was evaporated and crudewas purified by column chromatography (2M NH₃ in MeOH: CH₂Cl₂, 2:98 to5:95) on silica gel to obtain(R)-1-benzyl-N-(4-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indol-7-yl)-1H-pyrazole-4-carboxamide,compound #11, (0.025 g, 23%) as a yellow solid. ¹H NMR (DMSO-d₆) δ 1.31(d, 3H, J=3.3 Hz), 3.32-3.37 (m, 1H), 3.82-3.85 (m, 1H), 4.71-4.73 (m,1H), 5.41 (s, 2H), 6.98 (s, 1H), 7.29-7.39 (m, 6H), 7.60 (d, 1H, J=4.5Hz), 7.97 (d, 1H, J=2.4 Hz), 8.06 (d, 1H, J=1.8 Hz), 8.09 (s, 1H), 8.46(s, 1H), 9.94 (s, 1H).

Synthetic Example 12 Synthesis of1-benzyl-N-(1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indol-7-yl)-1H-pyrazole-4-carboxamide,Compound #12

A. A solution of methyl 6-bromo-1H-indole-2-carboxylate (compound 11a,0.865 g, 3.404 mmol) in dry DMF (10 mL) was treated with ^(t)BuOK (0.57g, 5.106 mmol) at room temperature and stirred for 15 minutes. Thereaction was treated with 2-bromoacetonitrile (compound 12a, 0.47 mL,6.808 mmol) drop-wise and was left to stir for 16 hours. The reactionwas quenched with the addition of saturated NH₄Cl solution (20 mL) anddiluted with water (100 mL). The brown solid was filtered off, washedwith water (2×75 mL), hexanes (25 mL) and dried under vacuum to obtainmethyl 6-bromo-1-(cyanomethyl)-1H-indole-2-carboxylate, compound 12b,(0.95 g, 95%).

B. A solution of methyl 6-bromo-1-(cyanomethyl)-1H-indole-2-carboxylate(compound 12b, 0.92 g, 3.138 mmol) in dry THF (15 mL) was treated withBH₃.THF (15.7 mL, 15.69 mmol, 1M solution in THF) drop-wise at 0° C. Thereaction was brought to room temperature and stirred for 24 hours. Thereaction was slowly quenched with methanol (10 mL) and then refluxed for30 minutes. The reaction was brought to room temperature, solvent wasevaporated and crude was purified by column chromatography (2M NH₃ inMeOH: CH₂Cl₂, 2.5:97.5) on silica gel to obtain7-bromo-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one, compound 12c, (0.27g, 34%) as a pale yellow solid. ¹H NMR (CDCl₃) δ 3.79-3.81 (m, 2H),4.20-4.22 (m, 2H), 6.59 (brs, 1H), 7.24-7.27 (m, 2H), 7.49 (s, 1H), 7.57(d, 1H, J=4.2 Hz).

C. A solution of Pd₂(dba)₃ (0.025 g, 0.043 mmol) in dry THF (5 mL) wastreated with P^(t)Bu₃ (0.51 mL, 0.173 mmol, 10% in hexanes) at roomtemperature. After stirring for 5 minutes, the reaction was treated witha solution of 7-bromo-3,4-dihydropyrazino[1,2-a]indol-1 (2H)-one(compound 12c, 0.23 g, 0.867 mmol) in dry THF (5 mL) followed by LiHMDS(1.74 mL, 1.735 mmol, 1M solution in THF). The resulting solution washeated at 100° C. in a sealed tube for 3 hours. The reaction was broughtto room temperature, quenched with 2 N HCl solution (10 mL) and stirredfor 10 minutes. The reaction was basified with 4N NaOH solution andproduct was extracted into ethyl acetate (2×50 mL). The combined ethylacetate layer was washed with brine (25 mL) and dried (Na₂SO₄). Solventwas evaporated and crude was purified by column chromatography (2M NH₃in MeOH: CH₂Cl₂, 2.5:97.5 to 5:95) on silica gel to obtain7-amino-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one, compound 12d, (0.09g, 52%) as a brown solid.

D. A solution of 7-amino-3,4-dihydropyrazino[1,2-a]indol-1(2H)-one(compound 12d, 0.09 g, 0.447 mmol), 1-benzyl-1H-pyrazole-4-carboxylicacid (compound 1c, 0.1 g, 0.491 mmol) and Et₃N (0.12 mL, 0.894 mmol) indry DMF (5 mL) was treated with HBTU (0.17 g, 0.447 mmol) at roomtemperature and stirred for 16 hours. The reaction was diluted with 1NNaOH solution (50 mL), water (50 mL) and product was extracted intoethyl acetate (2×50 mL). The combined ethyl acetate layer was washedwith brine (50 mL) and dried (Na₂SO₄). Solvent was evaporated and crudewas purified by column chromatography (2M NH₃ in MeOH:CH₂Cl₂, 2:98 to5:95) on silica gel to obtain1-benzyl-N-(1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indol-7-yl)-1H-pyrazole-4-carboxamide,compound #12, (0.008 g, 5%) as a yellow solid. ¹H NMR (DMSO-d₆) δ3.62-3.64 (m, 2H), 4.18-4.20 (m, 2H), 5.40 (s, 2H), 6.98 (s, 1H),7.29-7.39 (m, 6H), 7.60 (d, 1H, J=4.2 Hz), 8.05-8.08 (m, 3H), 8.46 (s,1H), 9.93 (s, 1H).

Synthetic Example 13 Synthesis of1-benzyl-N-(2-methyl-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridin-8-yl)-1H-pyrazole-4-carboxamide,Compound #13

A. A suspension of NaH (0.5 g, 12.872 mmol, 60% in mineral oil) in dryTHF (5 mL) was treated with 1-methylpiperidin-4-one oxime (compound 13a,prepared according to the methods disclosed in PCT Published PatentApplication No. WO 2006/108965, 1.5 g, 11.702 mmol) in dry THF (20 mL)drop-wise at 0° C. The reaction was brought to room temperature andstirred for 30 minutes. 1-Fluoro-4-nitrobenzene (compound 13b, 1.36 mL,12.872 mmol) followed by 18-crown-6 (0.12 g, 0.468 mmol) were added at0° C. and the reaction was brought to room temperature and stirred foradditional 4 hours. The reaction was quenched with water (50 mL) andproduct was extracted into ethyl acetate (2×50 mL). The combined ethylacetate layer was washed with brine (25 mL) and dried (Na₂SO₄). Solventwas evaporated and crude was purified by column chromatography (MeOH:CH₂Cl₂, 2:98) on silica gel to obtain 1-methylpiperidin-4-oneO-(4-nitrophenyl) oxime, compound 13c, (2.24 g, 77%) as a yellow solid.

B. Solid 1-methylpiperidin-4-one O-(4-nitrophenyl) oxime (compound 13c,1.0 g, 4.011 mmol) was added to flask containing PPA (˜50 mL) at 100° C.portion-wise and stirring was continued at same temperature foradditional 3 hours. The reaction was brought to 80° C. and diluted withwater (50 mL). The reaction was then brought to room temperature,basified with 4N NaOH solution and product was extracted into CH₂Cl₂(3×50 mL). The combined CH₂Cl₂ layer was dried (Na₂SO₄), solvent wasevaporated and crude was purified by column chromatography (2M NH₃ inMeOH: CH₂Cl₂, 2:98) on silica gel to obtain2-methyl-8-nitro-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine, compound13d, (0.24 g, 26%) as a yellow solid.

C. A solution of2-methyl-8-nitro-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridine (compound13d, 0.2 g, 0.861 mmol) in MeOH (10 mL) was treated with Raney-Nickel(˜50 mg) followed by hydrazine hydrate (0.41 mL, 8.611 mmol) at roomtemperature. The reaction was refluxed for 10-15 minutes in a pre-heatedoil bath and then brought back to room temperature. The solution wasfiltered through a pad of celite and washed with methanol (2×15 mL). Thecombined methanol layer was evaporated and crude was purified by flashcolumn chromatography (2M NH₃ in MeOH: CH₂Cl₂, 2:98 to 5:95) on silicagel to obtain2-methyl-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridin-8-amine, compound13e, (0.06 g, 35%) as a yellow solid.

D. A solution of2-methyl-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridin-8-amine (compound13e, 0.055 g, 0.271 mmol), 1-benzyl-1H-pyrazole-4-carboxylic acid(compound 1c, 0.06 g, 0.299 mmol) and Et₃N (0.075 mL, 0.543 mmol) in dryDMF (5 mL) was treated with HBTU (0.10 g, 0.271 mmol) at roomtemperature and stirred for 16 hours. The reaction was diluted with 1NNaOH solution (50 mL), water (50 mL) and product was extracted intoethyl acetate (2×50 mL). The combined ethyl acetate layer was washedwith brine (50 mL) and dried (Na₂SO₄). Solvent was evaporated and crudewas purified by column chromatography (2M NH₃ in MeOH: CH₂Cl₂, 2:98 to5:95) on silica gel to obtain1-benzyl-N-(2-methyl-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridin-8-yl)-1H-pyrazole-4-carboxamide,compound #13, (0.06 g, 57%) as an off-white solid. ¹H NMR (DMSO-d₆) δ2.43 (s, 3H), 2.77-2.80 (m, 4H), 3.47 (s, 2H), 5.39 (s, 2H), 7.28-7.38(m, 5H), 7.44-7.46 (m, 2H), 7.81 (s, 1H), 8.05 (s, 1H), 8.42 (s, 1H),9.84 (s, 1H).

Synthetic Example 14 Synthesis of1-benzyl-N-(2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)-1H-pyrazole-4-carboxamide,Compound #14

A. A solution of (4-nitrophenyl) hydrazine (compound 14a, 3.1 g, 20.24mmol) in 1,4-dioxane (25 mL) was treated with H₂SO₄ (2 mL) followed by1-methylpiperidin-4-one (compound 14b, 4.7 mL, 40.48 mmol) at roomtemperature and the resulting mixture was stirred at 80° C. for 30 min.The reaction was brought to room temperature, basified with 4N NaOHsolution and product was extracted into ethyl acetate (2×50 mL). Thecombined ethyl acetate layer was washed with brine (25 mL) and dried(Na₂SO₄). Solvent was evaporated and dried under vacuum to obtain1-methyl-4-(2-(4-nitrophenyl)hydrazono)piperidine, compound 14c, (4.5 g,90%) as a yellow solid.

B. Solid 1-methyl-4-(2-(4-nitrophenyl)hydrazono)piperidine (compound14c, 1.2 g, 4.83 mmol) was added to flask containing PPA (˜50 mL) at110° C. portion-wise and stirring was continued at same temperature foradditional 3 hours. The reaction was brought to 80° C. and diluted withwater (50 mL). The reaction was then brought to room temperature,basified with 4N NaOH solution and product was extracted into CH₂Cl₂(3×50 mL). The combined CH₂Cl₂ layer was dried (Na₂SO₄), solvent wasevaporated and crude was purified by column chromatography (2M NH₃ inMeOH: CH₂Cl₂, 2:98 to 3:97) on silica gel to obtain2-methyl-8-nitro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, compound14d, (0.24 g, 22%) as a yellow solid.

C. A solution of2-methyl-8-nitro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (compound14d, 0.15 g, 0.648 mmol) in MeOH (10 mL) was treated with Raney-Nickel(˜50 mg) followed by hydrazine hydrate (0.31 mL, 6.486 mmol) at roomtemperature. The reaction was refluxed for 10-15 minutes in a pre-heatedoil bath and then brought back to room temperature. The solution wasfiltered through a pad of celite and washed with methanol (2×15 mL). Thecombined methanol layer was evaporated and crude was purified by flashcolumn chromatography (2M NH₃ in MeOH: CH₂Cl₂, 2:98 to 5:95) on silicagel to obtain 2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-amine,compound 14e, (0.12 g, 92%) as a yellow solid.

D. A solution of2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-amine (compound 14e,0.11 g, 0.546 mmol), 1-benzyl-1H-pyrazole-4-carboxylic acid (compound1c, 0.12 g, 0.601 mmol) and Et₃N (0.15 mL, 1.093 mmol) in dry DMF (5 mL)was treated with HBTU (0.20 g, 0.546 mmol) at room temperature andstirred for 16 hours. The reaction was diluted with 1N NaOH solution (50mL), water (50 mL) and product was extracted into ethyl acetate (2×50mL). The combined ethyl acetate layer was washed with brine (50 mL) anddried (Na₂SO₄). Solvent was evaporated and crude was purified by columnchromatography (2M NH₃ in MeOH: CH₂Cl₂, 2:98 to 5:95) on silica gel toobtain1-benzyl-N-(2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)-1H-pyrazole-4-carboxamide,compound #14, (0.14 g, 67%) as an off-white solid. ¹H NMR (DMSO-d₆) δ2.42 (s, 3H), 2.71-2.77 (m, 4H), 3.48 (s, 2H), 5.38 (s, 2H), 7.18-7.38(m, 7H), 7.63 (s, 1H), 8.04 (s, 1H), 8.39 (s, 1H), 9.64 (s, 1H), 10.70(s, 1H).

Synthetic Example 15 Synthesis of(R)-1-benzyl-N-(9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-2-yl)-1H-pyrazole-4-carboxamide,Compound #15

A. A solution of methyl 6-bromo-1H-pyrrolo[2,3-b]pyridine-2-carboxylate(compound 15a, 0.5 g, 1.96 mmol) in dry DMF (10 mL) was treated with NaH(0.087 g, 2.16 mmol, 60% in mineral oil) at 0° C. and stirred at sametemperature for 30 additional minutes. The reaction was treated with asolution of tert-butyl (S)-5-methyl-1,2,3-oxathiazolidine-3-carboxylate2,2-dioxide (compound 11b, 0.49 g, 2.06 mmol) in DMF (10 mL) drop-wiseat same temperature. The reaction was brought to room temperature andstirred for 18 h. The reaction was quenched with the addition of water(50 mL) and product was extracted into ethyl acetate (2×25 mL). Thecombined ethyl acetate layer was washed with water (2×50 mL), brine (50mL) and dried (Na₂SO₄). Solvent was evaporated and obtained crudeproduct, methyl(R)-6-bromo-1-(1-((tert-butoxycarbonyl)amino)propan-2-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate,compound 15b, (0.75 g, 92%) as off-white solid, which was used directlyin the next step.

B. A solution of methyl(R)-6-bromo-1-(1-((tert-butoxycarbonyl)amino)propan-2-yl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate(compound 15b, 0.75 g, 1.82 mmol) in CH₂Cl₂ (50 mL) was treated with TFA(5 mL) at 0° C. The reaction was brought to room temperature and stirredfor 3 hours. Solvent was evaporated and crude was basified withsaturated NaHCO₃ solution (50 mL) and product was extracted into CH₂Cl₂(3×50 mL). The combined CH₂Cl₂ layer was dried (Na₂SO₄), solvent wasevaporated and crude was purified by column chromatography (MeOH:CH₂Cl₂, 0:100 to 10:90) on silica gel to obtain(R)-2-bromo-9-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one,compound 15c, (0.185 g, 36%) as a pale yellow solid. ¹H NMR (DMSO-d₆) δ1.46 (d, 3H, J=3.0 Hz), 3.42-3.45 (m, 1H), 3.93 (dd, 1H, J=4.8, 12.6Hz), 5.02-5.04 (m, 1H), 6.71 (s, 1H), 7.13 (s, 1H), 7.21 (d, 1H, J=8.8Hz), 7.80 (d, 1H, J=8.4 Hz).

C. A solution of Pd₂(dba)₃ (0.024 g, 0.014 mmol) in dry THF (5 mL) wastreated with P^(t)Bu₃ (0.5 mL, 0.167 mmol, 10% in hexanes) at roomtemperature. After stirring for 5 minutes, the reaction was treated witha solution of(R)-2-bromo-9-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one(compound 15c, 0.235 g, 0.839 mmol) in dry THF (10 mL) followed byLiHMDS (1.7 mL, 1.678 mmol, 1M solution in THF). The resulting solutionwas heated at 100° C. in a sealed tube for 3 hours. The reaction wasbrought to room temperature, quenched with 2 N HCl solution (10 mL) andstirred for 10 minutes. Reaction mixture extracted with ethyl acetate(2×25 mL) and recovered starting material (0.09 g, 38%). The aqueouslayer was basified with 4N NaOH solution and product was extracted intochloroform (4×30 mL). The combined chloroform layer was washed withbrine (25 mL) and dried (Na₂SO₄). Solvent was evaporated and crude waspurified by column chromatography (2M NH₃ in MeOH: CH₂Cl₂, 2.5:97.5 to10:90) on silica gel to obtain(R)-2-amino-9-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one,compound 15d, (0.09 g, 50%) as a brown solid. ¹H NMR (DMSO-d₆) δ 1.28(d, 3H, J=6.0 Hz), 3.28-3.32 (m, 1H), 3.73 (dd, 1H, J=4.8, 12.6 Hz),4.70-4.80 (m, 1H), 6.20 (s, 1H), 6.35 (d, 1H, J=8.4 Hz), 6.76 (s, 1H),7.74 (d, 1H, J=8.4 Hz).

D. A solution of(R)-2-amino-9-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one(compound 15d, 0.04 g, 0.185 mmol), 1-benzyl-1H-pyrazole-4-carboxylicacid (compound 1c, 0.038 g, 0.185 mmol) and diisopropyl ethylamine(0.043 g, 1.8 mmol) in dry DMF (3 mL) was treated with HATU (0.078 g,0.2 mmol) at room temperature. After 30 minutes stirring at roomtemperature, the reaction mixture was heated at 50° C. for 72 h. Thereaction was diluted with water (20 mL) and product was extracted intochloroform (3×25 mL). The combined chloroform layer was dried (Na₂SO₄).Solvent was evaporated and crude was purified by column chromatography(2M NH₃ in MeOH: CH₂Cl₂, 1:99 to 10:90) on silica gel to obtain(R)-1-benzyl-N-(9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-2-yl)-1H-pyrazole-4-carboxamide,compound #15, (0.015 g, 20%) as a off-white solid. ¹H NMR (DMSO-d₆) δ1.36 (d, 3H, J=6.6 Hz), 3.30-3.40 (m, 1H), 3.81-3.85 (m, 1H), 4.90-4.92(m, 1H), 5.39 (s, 2H), 6.99 (s, 1H), 7.30-7.39 (m, 5H), 8.02-8.19 (m,3H), 8.19 (s, 1H), 8.61 (s, 1H), 10.56 (s, 1H).

Synthetic Example 16 Synthesis of(R)—N-(1-(3-aminobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide,Compound #16

A. A solution of 4-nitropyrazole (compound 16a, 0.27 g, 2.45 mmol) andtert-butyl (3-(bromomethyl)phenyl)carbamate (compound 16b, 0.586 g, 2.04mmol) in acetone (10 mL) was treated with potassium carbonate (0.563 g,4.08 mmol) and heated to reflux temperature for 3 hours. The reactionwas brought to room temperature and solvent was evaporated on rotavapor.The reaction was diluted with the addition of water (30 mL) and productwas extracted into ethyl acetate (2×25 mL). The combined ethyl acetatelayer was washed with water (2×25 mL) and dried (Na₂SO₄). Solvent wasevaporated and crude product was purified through column using 10-30%ethyl acetate in hexanes and obtained tert-butyl(3-((4-nitro-1H-pyrazol-1-yl)methyl)phenyl)carbamate, compound 16c,(0.56 g, 95%) as off-white solid, which was used directly in the nextstep.

B. A solution of tert-butyl(3-((4-nitro-1H-pyrazol-1-yl)methyl)phenyl)carbamate (compound 16c, 0.2g, 0.69 mmol) in ethanol (2 mL) and water (1.5 mL) was treated with iron(0.115 g, 2.06 mmol) followed by acetic acid (0.042 g, 0.69 mmol).Reaction mixture was heated to reflux temperature for 2 hours. Thereaction was brought to room temperature and solvent was evaporated onrotavapor. The reaction was diluted with the addition of water (10 mL)and pH was adjusted to pH 7-8 using saturated sodium bicarbonatesolution. The product was extracted into dichloromethane (2×10 mL). Thecombined dichloromethane layer was washed with brine (10 mL) and dried(Na₂SO₄). Solvent was evaporated and the crude product, tert-butyl(3-((4-amino-1H-pyrazol-1-yl)methyl)phenyl)carbamate, compound 16d,(0.105 g, 58.6%) was obtained as light brown solid, which was useddirectly in the next step.

C. A solution of(R)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxylicacid (compound 16e, prepared according to the methods disclosed in PCTPublished Patent Application No. WO 2011/071725, 0.09 g, 0.367 mmol),tert-butyl (3-((4-amino-1H-pyrazol-1-yl)methyl)phenyl)carbamate(compound 16d, 0.105 g, 0.404 mmol) and diisopropyl ethylamine (0.153 g,0.404 mmol) in dry DMF (5 mL) was treated with HATU (0.085 g, 0.66 mmol)at room temperature. After stirring at room temperature overnight, thereaction was diluted with water (20 mL) and product was extracted intoethyl acetate (2×20 mL). The combined ethyl acetate layer was dried(Na₂SO₄). Solvent was evaporated and crude was purified by columnchromatography (2M NH₃ in MeOH: CH₂Cl₂, 1:99 to 10:90) on silica gel toobtain tert-butyl(R)-(3-((4-(9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamido)-1H-pyrazol-1-yl)methyl)phenyl)carbamate,compound 16f, (0.105 g, 55%) as a off-white solid.

D. A solution of tert-butyl(R)-(3-((4-(9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamido)-1H-pyrazol-1-yl)methyl)phenyl)carbamate(compound 16f 0.1 g, 0.194 mmol) in CH₂Cl₂ (10 mL) was treated with TFA(1 mL) at room temperature and stirred for additional 2 hours. Solventwas evaporated and crude was basified with 2N NaOH solution and productwas extracted into dichloromethane (2×15 mL). The combineddichloromethane layer was washed with brine (10 mL) and dried (Na₂SO₄).Solvent was evaporated and crude was purified by column chromatography(2M NH₃ in MeOH: CH₂Cl₂, 1:99 to 10:90) on silica gel to obtain(R)—N-(1-(3-aminobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide,compound #16 (0.065 g, 80.7%) as a off-white solid. ¹H NMR (DMSO-d₆) δ1.42 (d, 3H, J=6.6 Hz), 3.46-3.49 (m, 1H), 3.89-3.92 (m, 1H), 5.26 (s,2H), 5.26-5.28 (m, 1H), 6.72 (s, 1H), 6.77-6.79 (m, 2H), 7.13 (s, 1H),7.17 (d, 1H, J=7.8 Hz), 7.80 (s, 1H), 7.91 (d, 1H, J=8.4 Hz), 8.21 (s,1H), 8.30 (d, 1H, J=8.4 Hz), 8.35 (d, 1H, J=4.8 Hz), 10.67 (s, 1H).

Synthetic Example 17 Synthesis of(R)—N-(1-(2-aminobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide,Compound #17

A. A solution of 4-nitropyrazole (compound 16a, 0.236 g, 2.09 mmol) andtert-butyl (2-(bromomethyl)phenyl)carbamate (compound 17a, 0.5 g, 1.74mmol) in acetone (10 mL) was treated with potassium carbonate (0.48 g,3.48 mmol) and heated to reflux temperature for 3 hours. The reactionwas brought to room temperature and solvent was evaporated on rotavapor.The reaction was diluted with the addition of water (30 mL) and productwas extracted into ethyl acetate (2×25 mL). The combined ethyl acetatelayer was washed with water (2×25 mL) and dried (Na₂SO₄). Solvent wasevaporated and crude product was purified through column using 10-30%ethyl acetate in hexanes and obtained tert-butyl(2-((4-nitro-1H-pyrazol-1-yl)methyl)phenyl)carbamate, compound 17b,(0.48 g, 95%) as off-white solid, which was used directly in the nextstep.

B. A solution of tert-butyl(2-((4-nitro-1H-pyrazol-1-yl)methyl)phenyl)carbamate (compound 17b, 0.2g, 0.69 mmol) in ethanol (7 mL) and water (4 mL) was treated with iron(0.115 g, 2.06 mmol) followed by acetic acid (0.042 g, 0.69 mmol).Reaction mixture was heated to reflux temperature for 2 hours. Thereaction was brought to room temperature and solvent was evaporated onrotavapor. The reaction was diluted with the addition of water (10 mL)and pH was adjusted to pH 7-8 using saturated sodium bicarbonatesolution. Product was extracted into dichloromethane (2×10 mL). Thecombined dichloromethane layer was washed with brine (10 mL) and dried(Na₂SO₄). Solvent was evaporated and crude tert-butyl(2-((4-amino-1H-pyrazol-1-yl)methyl)phenyl)carbamate, compound 17c,(0.17 g, 94%) was obtained as orange solid, which was used directly inthe next step.

C. A solution of(R)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxylicacid (compound 16e, 0.09 g, 0.367 mmol), tert-butyl(2-((4-amino-1H-pyrazol-1-yl)methyl)phenyl)carbamate (compound 17c,0.105 g, 0.404 mmol) and diisopropyl ethylamine (0.153 g, 0.404 mmol) indry DMF (5 mL) was treated with HATU (0.085 g, 0.66 mmol) at roomtemperature. After stirring at room temperature overnight, the reactionwas diluted with water (20 mL) and product was extracted into ethylacetate (2×20 mL). The combined ethyl acetate layer was dried (Na₂SO₄).Solvent was evaporated and crude was purified by column chromatography(2M NH₃ in MeOH: CH₂Cl₂, 1:99 to 6:94) on silica gel to obtaintert-butyl(R)-(2-((4-(9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamido)-1H-pyrazol-1-yl)methyl)phenyl)carbamate,compound 17d, (0.16 g, 84.6%) as a light brown solid.

D. A solution of tert-butyl(R)-(2-((4-(9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamido)-1H-pyrazol-1-yl)methyl)phenyl)carbamate(compound 17d, 0.16 g, 0.31 mmol) in CH₂Cl₂ (10 mL) was treated with TFA(1 mL) at room temperature and stirred for additional 2 hours. Solventwas evaporated and crude was basified with 2N NaOH solution and productwas extracted into dichloromethane (2×15 mL). The combineddichloromethane layer was washed with brine (10 mL) and dried (Na₂SO₄).Solvent was evaporated and crude was purified by column chromatography(2M NH₃ in MeOH: CH₂Cl₂, 1:99 to 8:92) on silica gel to obtain(R)—N-(1-(2-aminobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide,compound #17, (0.08 g, 62%) as a pale yellow solid. ¹H NMR (DMSO-d₆) δ1.41 (d, 3H, J=6.6 Hz), 3.45-3.48 (m, 1H), 3.88-3.91 (m, 1H), 5.19 (s,2H), 5.22-5.28 (m, 1H), 6.53-6.55 (m, 1H), 6.67-6.68 (m, 1H), 6.97-7.03(m, 2H), 7.12 (s, 1H), 7.79 (s, 1H), 7.90 (d, 1H, J=8.4 Hz), 8.16 (s,1H), 8.29 (d, 1H, J=8.4 Hz), 8.34 (d, 1H, J=4.8 Hz), 10.64 (s, 1H).

Synthetic Example 18 Synthesis of(R)—N-(1-(4-aminobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide,Compound #18

A. A solution of 4-nitropyrazole (compound 16a, 0.236 g, 2.09 mmol) andtert-butyl (4-(bromomethyl)phenyl)carbamate (compound 18a, 0.5 g, 1.74mmol) in acetone (10 mL) was treated with potassium carbonate (0.48 g,3.48 mmol) and heated to reflux temperature for 3 hours. The reactionwas brought to room temperature and solvent was evaporated on rotavapor.The reaction was diluted with the addition of water (30 mL) and productwas extracted into ethyl acetate (2×25 mL). The combined ethyl acetatelayer was washed with water (2×25 mL) and dried (Na₂SO₄). Solvent wasevaporated and crude product was purified through column using 10-30%ethyl acetate in hexanes and obtained tert-butyl(4-((4-nitro-1H-pyrazol-1-yl)methyl)phenyl)carbamate, compound 18b,(0.46 g, 91%) as pale yellow thick liquid, which was used directly inthe next step.

B. A solution of tert-butyl(4-((4-nitro-1H-pyrazol-1-yl)methyl)phenyl)carbamate (compound 18b, 0.2g, 0.69 mmol) in ethanol (5 mL) and water (2 mL) was treated with iron(0.115 g, 2.06 mmol) followed by acetic acid (0.042 g, 0.69 mmol).Reaction mixture was heated to reflux temperature for 2 hours. Thereaction was brought to room temperature and solvent was evaporated onrotavapor. The reaction was diluted with the addition of water (10 mL)and pH was adjusted to pH 7-8 using saturated sodium bicarbonatesolution. Product was extracted into dichloromethane (2×10 mL). Thecombined dichloromethane layer was washed with brine (10 mL) and dried(Na₂SO₄). Solvent was evaporated and crude tert-butyl(4-((4-amino-1H-pyrazol-1-yl)methyl)phenyl)carbamate, compound 18c,(0.17 g, 94%) was obtained as orange solid, which was used directly inthe next step.

C. A solution of(R)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxylicacid (compound 16e, 0.09 g, 0.367 mmol), tert-butyl(4-((4-amino-1H-pyrazol-1-yl)methyl)phenyl)carbamate (compound 18c,0.105 g, 0.404 mmol) and diisopropyl ethylamine (0.153 g, 0.404 mmol) indry DMF (5 mL) was treated with HATU (0.085 g, 0.66 mmol) at roomtemperature. After stirring at room temperature overnight, the reactionwas diluted with water (20 mL) and product was extracted into ethylacetate (2×20 mL). The combined ethyl acetate layer was dried (Na₂SO₄).Solvent was evaporated and crude was purified by column chromatography(2M NH₃ in MeOH: CH₂Cl₂, 1:99 to 6:94) on silica gel to obtaintert-butyl(R)-(4-((4-(9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamido)-1H-pyrazol-1-yl)methyl)phenyl)carbamate,compound 18d, (0.167 g, 88.8%) as a off-white solid.

D. A solution of tert-butyl(R)-(4-((4-(9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamido)-1H-pyrazol-1-yl)methyl)phenyl)carbamate(compound 18d, 0.158 g, 0.306 mmol) in CH₂Cl₂ (10 mL) was treated withTFA (1 mL) at room temperature and stirred for additional 2 hours.Solvent was evaporated and crude was basified with 2N NaOH solution andproduct was extracted into dichloromethane (2×15 mL). The combineddichloromethane layer was washed with brine (10 mL) and dried (Na₂SO₄).Solvent was evaporated and crude was purified by column chromatography(2M NH₃ in MeOH: CH₂Cl₂, 1:99 to 8:92) on silica gel to obtain(R)—N-(1-(4-aminobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide,compound #18, (0.065 g, 80.7%) as a off-white solid. ¹H NMR (DMSO-d₆) δ1.42 (d, 3H, J=6.6 Hz), 3.45-3.48 (m, 1H), 3.89-3.92 (m, 1H), 5.09 (s,2H), 5.27-5.29 (m, 1H), 6.52-6.54 (m, 2H), 6.77-6.79 (m, 2H), 7.0-7.02(m, 2H), 7.12 (s, 1H), 7.74 (s, 1H), 7.90 (d, 1H, J=7.8 Hz), 8.07 (s,1H), 8.29 (d, 1H, J=7.8 Hz), 8.34 (d, 1H, J=4.8 Hz), 10.61 (s, 1H).

Synthetic Example 19 Synthesis of(R)-1-(3-aminobenzyl)-N-(9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-2-yl)-1H-pyrazole-4-carboxamide,Compound #19

A. A solution of ethyl 1H-pyrazole-4-carboxylate (compound 19a, 0.25 g,1.78 mmol) and tert-butyl (3-(bromomethyl)phenyl)carbamate (compound16b, 0.51 g, 1.78 mmol) in acetone (10 mL) was treated with potassiumcarbonate (0.48 g, 3.48 mmol) and heated to reflux temperature for 3hours. The reaction was brought to room temperature and solvent wasevaporated on rotavapor. The reaction was diluted with the addition ofwater (30 mL) and product was extracted into ethyl acetate (2×25 mL).The combined ethyl acetate layer was washed with water (2×25 mL) anddried (Na₂SO₄). Solvent was evaporated and crude product was purifiedthrough column using 10-30% ethyl acetate in hexanes and obtained ethyl1-(3-((tert-butoxycarbonyl)amino)benzyl)-1H-pyrazole-4-carboxylate,compound 19b, (0.635 g, 100%) as off-white solid, which was useddirectly in the next step.

B. A solution of ethyl1-(3-((tert-butoxycarbonyl)amino)benzyl)-1H-pyrazole-4-carboxylate(compound 19b, 0.635 g, 1.78 mmol) in methanol (20 mL) and water (10 mL)was treated with LiOH.H₂O (0.15 g, 3.55 mmol). Reaction mixture wasstirred at room temperature for 24 hours. Solvent was evaporated onrotavapor. The reaction was diluted with the addition of water (10 mL)and pH was adjusted to pH 5 using acetic acid. Product was extractedinto dichloromethane (2×10 mL). The combined dichloromethane layer waswashed with brine (10 mL) and dried (Na₂SO₄). Solvent was evaporated andcrude 1-(3-((tert-butoxycarbonyl)amino)benzyl)-1H-pyrazole-4-carboxylicacid, compound 19c, (0.525 g, 90%) was obtained as white solid, whichwas used directly in the next step.

C. A solution of(R)-2-amino-9-methyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one(compound 15d, 0.08 g, 0.24 mmol),1-(3-((tert-butoxycarbonyl)amino)benzyl)-1H-pyrazole-4-carboxylic acid(compound 19c, 0.53 g, 0.24 mmol) and diisopropyl ethylamine (0.075 g,0.57 mmol) in dry DMF (5 mL) was treated with BOP (0.212 g, 0.48 mmol)at room temperature. After stirring at 50° C. temperature for 7 days,the reaction was diluted with water (20 mL) and product was extractedinto ethyl acetate (2×20 mL). The combined ethyl acetate layer was dried(Na₂SO₄). Solvent was evaporated and crude was purified by columnchromatography (2M NH₃ in MeOH: CH₂Cl₂, 1:99 to 5:95) on silica gel toobtain tert-butyl(R)-(3-((4-((9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-2-yl)carbamoyl)-1H-pyrazol-1-yl)methyl)phenyl)carbamate,compound 19d, (0.008 g, 6.4%) as a light brown solid.

D. A solution of tert-butyl(R)-(3-((4-((9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-2-yl)carbamoyl)-1H-pyrazol-1-yl)methyl)phenyl)carbamate(compound 19d, 0.008 g, 0.0155 mmol) in CH₂Cl₂ (10 mL) was treated withTFA (0.5 mL) at room temperature and stirred for additional 2 hours.Solvent was evaporated and crude was basified with 2N NaOH solution andproduct was extracted into dichloromethane (2×10 mL). The combineddichloromethane layer was washed with brine (5 mL) and dried (Na₂SO₄).Solvent was evaporated and crude was purified by column chromatography(2M NH₃ in MeOH: CH₂Cl₂, 1:99 to 6:94) on silica gel to obtain(R)-1-(3-aminobenzyl)-N-(9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-2-yl)-1H-pyrazole-4-carboxamide,compound #19, (0.003 g, 46%) as a light brown solid. ¹H NMR (CDCl₃) δ1.43 (d, 3H, J=6.4 Hz), 3.39-3.42 (m, 1H), 3.92-3.96 (m, 1H), 4.85-4.90(m, 1H), 5.18 (s, 2H), 5.94 (s, 1H), 6.50 (d, 1H, J=2 Hz), 6.58-6.61 (m,2H), 7.07-7.13 (m, 2H), 7.91-7.98 (m, 3H), 8.13 (d, 1H, J=8.8 Hz).

Synthetic Example 20 Synthesis of(R)-9-methyl-N-(1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide,Compound #20

A. A solution of 4-nitro-1H-pyrazole (0.5 g, 4.421 mmol),(1-methylpiperidin-4-yl)methanol (0.57 g, 4.421 mmol) andtriphenylphosphine (1.27 g, 4.863 mmol) in dry THF (20 mL) was treatedwith DTAD (1.22 g, 5.305 mmol) at room temperature and was stirred foradditional 4 h. Solvent was evaporated and crude was purified by columnchromatography (dichloromethane to MeOH: Dichloromethane, 1:99 to 5:95to 2M NH₃ in MeOH:dichloromethane, 5:95 to 1:9) on silica gel to obtainthe title compound (0.34 g, 34%) as an off-white solid.

B. A solution of 1-methyl-4-((4-nitro-1H-pyrazol-1-yl)methyl)piperidine(0.33 g, 1.471 mmol) in methanol (5 mL) was treated with palladium oncarbon (0.05 g) and purged with hydrogen gas. The flask was evacuatedand filled with hydrogen gas (three times) and stirred under hydrogenatm. (balloon pressure) for additional 3 h. The reaction was filteredthrough a pad of celite and washed with methanol (3×20 mL). The combinedmethanol layer was evaporated to obtain the title compound (0.27 g, 95%)as a light brown solid. ¹H NMR (CDCl₃) δ 1.24-1.28 (m, 2H), 1.51-1.55(m, 2H), 1.81-1.87 (m, 3H), 2.21 (s, 3H), 2.78-2.84 (m, 4H), 3.82 (d,2H, J=5.4 Hz), 6.95 (s, 1H), 7.12 (s, 1H).

C. A solution of(R)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxylicacid (0.05 g, 0.203 mmol),1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-amine (0.04 g, 0.203mmol) and DIPEA (0.06 mL, 0.366 mmol) in dry DMF (5 mL) was treated withHATU (0.09 g, 0.234 mmol) at room temperature and stirred for additional24 h. The reaction was diluted with water (50 mL), basified with 2 NNaOH solution (20 mL) and product was extracted into ethyl acetate (3×50mL). The combined ethyl acetate layer was washed with water (2×25 mL),brine (50 mL) and dried (Na₂SO₄). Solvent was evaporated and crude waspurified by column chromatography (2 M NH₃ in MeOH: Dichloromethane,5:95 to 1:9) on silica gel to obtain the title compound (0.06 g, 71%) asa pale yellow solid. ¹H NMR (DMSO-d₆) δ 1.34-1.43 (m, 2H), 1.43 (d, 3H,J=3.3 Hz), 1.61 (d, 2H, J=6.0 Hz), 1.95 (brs, 1H), 2.55 (s, 3H),3.13-3.50 (m, 5H), 3.91 (dd, 1H, J=2.1, 6.4 Hz), 4.06 (d, 2H, J=3.6 Hz),5.27-5.29 (m, 1H), 7.13 (s, 1H), 7.76 (d, 1H, J=0.3 Hz), 7.92 (d, 1H,J=3.9 Hz), 8.18 (s, 1H), 8.30 (d, 1H, J=4.2 Hz), 8.34 (d, 1H, J=2.7 Hz),10.62 (s, 1H).

Synthetic Example 21 Synthesis of(R)—N-(2-carbamoylphenyl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide,Compound #21

A solution of(R)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxylicacid (0.05 g, 0.203 mmol), 2-aminobenzamide (0.027 g, 0.203 mmol) andDIPEA (0.06 mL, 0.366 mmol) in dry DMF (5 mL) was treated with HATU(0.09 g, 0.234 mmol) at room temperature and stirred for additional 24h. The reaction was diluted with water (50 mL), basified with 2 N NaOHsolution (20 mL) and product was extracted into ethyl acetate (3×50 mL).The combined ethyl acetate layer was washed with water (2×25 mL), brine(50 mL) and dried (Na₂SO₄). Solvent was evaporated and crude waspurified by column chromatography (2 M NH₃ in MeOH: Dichloromethane,5:95 to 1:9) on silica gel to obtain the title compound (19 mg, 26%) asa pale yellow solid. ¹H NMR (DMSO-d₆) δ 1.51 (d, 3H, J=3.3 Hz),3.47-3.50 (m, 1H), 3.95-3.98 (m, 1H), 5.19-5.21 (m, 1H), 7.17-7.20 (m,2H), 7.56-7.59 (m, 1H), 7.73 (s, 1H), 7.86 (dd, 1H, J=0.6, 3.9 Hz), 8.00(d, 1H, J=4.2 Hz), 8.26 (brs, 1H), 8.35 (d, 1H, J=4.2 Hz), 8.40 (d, 1H,J=2.4 Hz), 8.78 (dd, 1H, J=0.3, 4.2 Hz), 13.48 (s, 1H).

Synthetic Example 22 Synthesis of(R)-9-methyl-6-oxo-N-(1-(4-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide,Compound #22

A. A solution of 4-nitro-1H-pyrazole (5.0 g, 44.216 mmol) and1-(bromomethyl)-4-(trifluoromethyl)benzene (11.09 g, 46.427 mmol) inacetone (100 mL) was treated with potassium carbonate (30.5 g, 221.082mmol) and heated at reflux temperature for 2 h. The reaction was broughtto room temperature; solid was filtered off and washed withdichloromethane (3×35 mL). Combined organic layer was evaporated and thecrude product was washed with hexanes to obtain the title compound (12.0g, quantitative) as a white solid.

B. A solution of 4-nitro-1-(4-(trifluoromethyl)benzyl)-1H-pyrazole(2.5.0 g, 7.743 mmol) in ethanol (30 mL) and water (25 mL) was treatedwith iron (1.29 g, 23.229 mmol) followed by acetic acid (0.44 mg, 7.743mmol) and the reaction was heated at reflux temperature for 2 h. Thereaction was brought to room temperature and solvent was evaporated. Thereaction was basified with 1 N NaOH solution and product was extractedinto dichloromethane (3×50 mL). The combined dichloromethane layer waswashed with brine (10 mL) and dried (Na₂SO₄). Solvent was evaporated andcrude was purified by column chromatography (2 M NH₃ in MeOH:Dichloromethane, 5:95) on silica gel to obtain the title compound (1.75g, 94%) as an orange-red solid.

C. A solution of(R)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxylicacid (0.05 g, 0.203 mmol),1-(4-(trifluoromethyl)benzyl)-1H-pyrazol-4-amine (0.049 g, 0.203 mmol)and DIPEA (0.06 m t, 0.366 mmol) in dry DMF (5 mL) was treated with HATU(0.09 g, 0.234 mmol) at room temperature and stirred for additional 24h. The reaction was diluted with water (50 mL), basified with 2 N NaOHsolution (20 mL) and product was extracted into ethyl acetate (3×50 m).The combined ethyl acetate layer was washed with water (2×25 mL), brine(50 mL) and dried (Na₂SO₄). Solvent was evaporated and crude waspurified by column chromatography (2 M NH₃ in MeOH: Dichloromethane,5:95 to 1:9) on silica gel to obtain the title compound (65 mg, 68%) asa pale yellow solid. ¹H NMR (DMSO-d₆) δ 1.44 (d, 3H, J=3.3 Hz),3.47-3.50 (m, 1H), 3.90-3.93 (m, 1H), 5.28-5.30 (m, 1H), 5.48 (s, 2H),7.14 (s, 1H), 7.45 (d, 2H, J=4.2 Hz), 7.73 (d, 2H, J=4.2 Hz), 7.85 (s,1H), 7.94 (d, 1H, J=3.9 Hz), 8.29-8.37 (m, 3H), 10.70 (s, 1H).

Synthetic Example 23 Synthesis of(R)—N-(1-(2,4-difluorobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide,Compound #23

A. A solution of 4-nitro-1H-pyrazole (3.0 g, 26.529 mmol) and1-(bromomethyl)-2,4-difluorobenzene (5.76 g, 27.856 mmol) in acetone (60mL) was treated with potassium carbonate (18.33 g, 132.649 mmol) andheated at reflux temperature for 2 h. The reaction was brought to roomtemperature; solid was filtered off and washed with dichloromethane(3×25 mL). Combined organic layer was evaporated and the crude productwas washed with hexanes to obtain the title compound (6.3 g,quantitative) as an off-white solid.

B. A solution of 1-(2,4-difluorobenzyl)-4-nitro-1H-pyrazole (2.1 g,8.779 mmol) in ethanol (25 mL) and water (20 mL) was treated with iron(1.47 g, 26.339 mmol) followed by acetic acid (0.5 mL, 8.779 mmol) andthe reaction was heated at reflux temperature for 2 h. The reaction wasbrought to room temperature and solvent was evaporated. The reaction wasbasified with 1 N NaOH solution and product was extracted intodichloromethane (3×50 mL). The combined dichloromethane layer was washedwith brine (10 mL) and dried (Na₂SO₄). Solvent was evaporated and crudewas purified by column chromatography (2 M NH₃ in MeOH:Dichloromethane,5:95) on silica gel to obtain the title compound (1.42 g, 78%) as a darkred solid.

C. A solution of(R)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxylicacid (0.05 g, 0.203 mmol), 1-(2,4-difluorobenzyl)-1H-pyrazol-4-amine(0.043 g, 0.203 mmol) and DIPEA (0.06 mL, 0.366 mmol) in dry DMF (5 mL)was treated with HATU (0.09 g, 0.234 mmol) at room temperature andstirred for additional 24 h. The reaction was diluted with water (50mL), basified with 2 N NaOH solution (20 mL) and product was extractedinto ethyl acetate (3×50 mL). The combined ethyl acetate layer waswashed with water (2×25 mL), brine (50 mL) and dried (Na₂SO₄). Solventwas evaporated and crude was purified by column chromatography (2 M NH₃in MeOH: Dichloromethane, 5:95 to 1:9) on silica gel to obtain the titlecompound (40 mg, 45%) as a pale yellow solid. ¹H NMR (DMSO-d₆) δ 1.43(d, 3H, J=3.3 Hz), 3.47-3.50 (m, 1H), 3.90-3.93 (m, 1H), 5.28-5.30 (m,1H), 5.39 (s, 2H), 7.09-7.37 (m, 4H), 7.81 (s, 1H), 7.93 (d, 1H, J=4.2Hz), 8.25-8.37 (m, 3H), 10.68 (s, 1H).

Synthetic Example 24 Synthesis of(R)—N-(1-benzyl-1H-pyrazol-4-yl)-5-chloro-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide,Compound #24

A. A suspension of diethyl 1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylate(0.102 g, 0.388 mmol) in acetonitrile (5 mL) was treated withN-chlorosuccinamide (0.062 g, 0.466 mmol) and the resulting solution wasstirred at 60° C. for 24 h. The reaction was brought to roomtemperature, diluted with water (50 mL) and the product was extractedinto ethyl acetate (2×25 mL). The combined ethyl acetate layer waswashed with brine (20 mL) and dried (Na₂SO₄). Solvent was evaporated andcrude was purified by flash column chromatography (EtOAc:Hexanes, 1:9 to1:4) on silica gel to obtain the title compound (0.1 g, 87%) as acolorless oil.

B. A solution of diethyl3-chloro-1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylate (0.1 g, 0.337 mmol)in dry DMF (3 mL) was treated with sodium hydride (14.2 mg, 0.370 mmol,60% in mineral oil) at 0° C. The reaction was brought to roomtemperature and stirred for 30 min. A solution of tert-butyl(S)-5-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (83 mg,0.353 mmol) in dry DMF (2 mL) was added and the reaction was stirred atroom temperature for 18 h. The reaction was diluted with water (30 mL),acidified with 0.5 M citric acid (20 mL) and the product was extractedinto diethyl ether (2×25 mL). The combined diethyl ether layer waswashed with water (25 mL), brine (20 mL) and dried (Na₂SO₄). Diethylether was evaporated to obtain the title compound (0.12 g, 79%) as anoil.

C. A solution of diethyl(R)-1-(1-((tert-butoxycarbonyl)amino)propan-2-yl)-3-chloro-1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylate(0.12 g, 0.264 mmol) in methanol (5 mL) was treated with 4 M HCl in1,4-dioxane (0.33 mL, 1.321 mmol) at room temperature and stirred foradditional 16 h. Solvent was evaporated, crude was taken indichloromethane (50 mL) and washed with sat. NaHCO₃ solution (20 mL).The aqueous layer was further extracted with dichloromethane (2×20 mL).The combined dichloromethane layer was dried (Na₂SO₄) and solvent wasevaporated to obtain the crude title compound (76 mg, 82%) as a paleyellow solid.

D. A solution of diethyl(R)-1-(1-aminopropan-2-yl)-3-chloro-1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylate(76 mg, 0.214 mmol) in ethanol (3 mL) was treated with potassiumcarbonate (89 mg, 0.644 mmol) and the resulting mixture was heated at60° C. for additional 16 h. The reaction was brought to room temperatureand solvent was evaporated. The crude was diluted with water (15 mL),acidified with citric acid and product was extracted intodichloromethane (3×20 mL). The combined dichloromethane layer was dried(Na₂SO₄) and solvent was evaporated to obtain the title compound (50 mg,83%) as an off-white solid.

E. A solution of(R)-5-chloro-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxylicacid (0.05 g, 0.178 mmol), 1-benzyl-1H-pyrazol-4-amine (0.03 g, 0.178mmol) and DIPEA (0.056 mL, 0.321 mmol) in DMF (5 mL) was treated withHATU (0.078 g, 0.205 mmol) at room temperature and stirred foradditional 24 h. The reaction was diluted with water (50 mL), basifiedwith 2 N NaOH solution (20 mL) and product was extracted into ethylacetate (3×50 mL). The combined ethyl acetate layer was washed withwater (2×25 mL), brine (50 mL) and dried (Na₂SO₄). Solvent wasevaporated and crude was purified by column chromatography (2 M NH₃ inMeOH:Dichloromethane, 5:95 to 1:9) on silica gel to obtain the titlecompound (40 mg, 45%) as a tan solid. ¹H NMR (DMSO-d₆) δ 1.44 (d, 3H,J=3.3 Hz), 3.45-3.47 (m, 1H), 3.90-3.93 (m, 1H), 5.32-5.36 (m, 3H),7.27-7.37 (m, 5H), 7.80 (s, 1H), 7.99 (d, 1H, J=3.9 Hz), 8.24-8.28 (m,2H), 8.45 (d, 1H, J=2.7 Hz), 10.73 (s, 1H).

Synthetic Example 25 Synthesis of(R)—N-(1-(4-aminobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamidehydrochloride salt, Compound #25

A. A solution of the Compound 18 (1.0 equivalent) in MeOH was treatedwith HCl in ether (1M solution, 1.5 equivalent) at room temperature andstirred for 30 min. The solvent was evaporated and dried under vacuum toobtain Compound 25.

Synthetic Example 26 Synthesis of(R)—N-(1-(4-(aminomethyl)benzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamidehydrochloride salt, Compound #26

A. A solution of 4-nitro-1H-pyrazole (0.23 g, 2.048 mmol) and tert-butyl(4-(bromomethyl)benzyl)carbamate (0.615 g, 2.048 mmol) in acetone (10mL) was treated with potassium carbonate (0.85 g, 6.145 mmol) and heatedat reflux temperature for 2 h. The reaction was brought to roomtemperature; solid was filtered off and washed with dichloromethane(3×25 mL). Combined organic layer was evaporated and the crude productwas washed with hexanes to obtain the title compound (0.68 g,quantitative) as an off-white solid.

B. A solution of tert-butyl(4-((4-nitro-1H-pyrazol-1-yl)methyl)benzyl)carbamate (0.68 g, 2.045mmol) in ethanol (10 mL) and water (7 mL) was treated with iron (0.34 g,6.137 mmol) followed by acetic acid (0.12 mL, 2.045 mmol) and thereaction was heated at reflux temperature for 2 h. The reaction wasbrought to room temperature and solvent was evaporated. The reaction wasbasified with 1 N NaOH solution and product was extracted intodichloromethane (3×50 mL). The combined dichloromethane layer was washedwith brine (10 mL) and dried (Na₂SO₄). Solvent was evaporated and crudewas purified by column chromatography (2 M NH₃ in MeOH: Dichloromethane,5:95) on silica gel to obtain the title compound (0.45 g, 73%) as abrown solid.

C. A solution of(R)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxylicacid (0.11 g, 0.448 mmol), tert-butyl(4-((4-amino-1H-pyrazol-1-yl)methyl)benzyl)carbamate (0.135 g, 0.448mmol) and DIPEA (0.14 mL, 0.807 mmol) in dry DMF (5 mL) was treated withHATU (0.196 g, 0.515 mmol) at room temperature and stirred foradditional 24 h. The reaction was diluted with water (50 mL), basifiedwith 2 N NaOH solution (20 mL) and product was extracted into ethylacetate (3×50 mL). The combined ethyl acetate layer was washed withwater (2×25 mL), brine (50 mL) and dried (Na₂SO₄). Solvent wasevaporated and crude was purified by column chromatography (2 M NH₃ inMeOH:Dichloromethane, 1:99 to 5:95) on silica gel to obtain the titlecompound (170 mg, 72%) as a light brown solid.

D. A solution of tert-butyl(R)-(4-((4-(9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamido)-1H-pyrazol-1-yl)methyl)benzyl)carbamate(0.17 g, 0.32 mmol) in CH₂Cl₂ (6 mL) was treated with TFA (4 mL) at roomtemperature and stirred for additional 2 h. Solvent was evaporated andcrude was basified with 2N NaOH solution and product was extracted intodichloromethane (2×15 mL). The combined dichloromethane layer was washedwith brine (10 mL) and dried (Na₂SO₄). Solvent was evaporated and crudewas purified by column chromatography (2M NH₃ in MeOH:CH₂Cl₂, 1:99 to1:9) on silica gel to obtain(R)—N-(1-(4-(aminomethyl)benzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide(0.13 g, 95%) which was converted to the mono-hydrochloride salt,Compound 26, by the procedure described in Example 25. ¹H NMR spectrumfor Compound 26 (DMSO-d₆) δ 1.42 (d, 3H, J=5.1 Hz), 3.45-3.50 (m, 1H),3.88-4.01 (m, 3H), 5.27-5.35 (m, 3H), 7.13 (s, 1H), 7.31 (d, 2H, J=6.0Hz), 7.47 (d, 2H, J=6.0 Hz), 7.78 (s, 1H), 7.90 (d, 1H, J=6.3 Hz),8.24-8.41 (m, 6H), 10.68 (s, 1H).

In a similar manner as described above in Synthetic Examples 1-26, butusing the appropriately substituted starting materials, the followingcompounds are prepared:

-   (R)—N-(1-benzyl-1H-pyrazol-4-yl)-5-fluoro-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;-   (R)—N-(1-benzyl-1H-pyrazol-4-yl)-9-isopropyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;-   (S)—N-(1-benzyl-1H-pyrazol-4-yl)-9-trifluoromethyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;-   N-(1-benzyl-1H-pyrazol-4-yl)-6′-oxo-7′,8′-dihydro-6′H-spiro[cyclopropane-1,9′-pyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine]-2′-carboxamide;-   (R)—N-(1-(4-methylpiperazinyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;-   (S)—N-(1-benzyl-1H-pyrazol-4-yl)-9-isopropyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;-   (R)—N-(1-benzyl-1H-pyrazol-4-yl)-9-trifluoromethyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;-   N-(1-benzyl-1H-pyrazol-4-yl)-9,9-dimethyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;-   (S)—N-(1-benzyl-1H-pyrazol-4-yl)-6-methyl-9-oxo-6,7,8,9-tetrahydropyrido[2′,3′:4,5]pyrrolo[1,2-a]pyrazine-3-carboxamide;-   (S)—N-(1-benzyl-1H-pyrazol-4-yl)-6-methyl-9-oxo-6,7,8,9-tetrahydropyrido[2′,3′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;-   (S)-1-benzyl-N-(6-methyl-9-oxo-6,7,8,9-tetrahydropyrido[2′,3′:4,5]pyrrolo[1,2-a]pyrazin-3-yl)-1H-pyrazole-4-carboxamide;-   (S)-1-benzyl-N-(6-methyl-9-oxo-6,7,8,9-tetrahydropyrido[2′,3′:4,5]pyrrolo[1,2-a]pyrazin-2-yl)-1H-pyrazole-4-carboxamide;-   (R)-5-fluoro-9-methyl-N-(1-((4-methylpiperazin-1-yl)methyl)-1H-pyrazol-4-yl)-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;-   (R)-5-fluoro-9-methyl-N-(1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;-   (R)—N-(1-benzyl-1H-pyrazol-4-yl)-6-methyl-9-oxo-6,7,8,9-tetrahydropyrrolo[1,5-a:2,3-b′]dipyrazine-3-carboxamide;-   (R)-1-(1-benzyl-1H-pyrazol-4-yl)-3-(9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-2-yl)urea;    and-   (R)-1-(1-benzyl-1H-pyrazol-4-yl)-3-(9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-2-yl)guanidine.

General Synthetic Procedure General Procedure for Converting Compoundsin Free Base Form to Mono- or Di-Hydrochloride Salts

A solution of a compound described herein as a free base (1.0equivalent) in MeOH or a mixture of MeOH:CH₂Cl₂ (3:2) was treated withHCl in ether (1M solution, 1.5 equivalent for mono-hydrochloride saltand 3.0 equivalent for di-hydrochloride salt) at room temperature andstirred for additional 30 minutes at same temperature. Solvent wasevaporated and dried under vacuum to obtain the required mono- ordi-hydrochloride salt of the corresponding free base.

BIOLOGICAL EXAMPLES

Various techniques are known in the art for testing the activity of thecompounds described herein in various in vitro and in vivo assays. Inorder that the invention described herein may be more fully understood,the following Biological Examples are set forth. It should be understoodthat these examples are for illustrative purposes only and are not to beconstrued as limiting this invention in any manner.

Biological Example 1 Kinase Assays to Determine the Structure ActivityRelationship (SAR) of RSK Inhibitors

The assay conditions for the RSK2 kinase target were optimized to yieldacceptable enzymatic activity. In addition, the assays were optimized togive high signal-to-noise ratio.

Radioisotope assays (SignalChem) were performed for the evaluation ofthe kinase target profiling and all assays were performed in adesignated radioactive working area. The kinase targets were RSK1, RSK2,RSK3, RSK4 and MK2. The kinase assays (in duplicate) were performed at30° C. for 15 minutes in a final volume of 25 μL according to thefollowing assay reaction recipe:

-   Component 1: 5 μL of diluted active kinase target (100 ng per    reaction)-   Component 2: 5 μL of peptide substrate (0.5 μg per reaction) (for    RSK1, RSK2, RSK3 and RSK4, RSK S6K substrate was used; for MK2,    HSP27tide was used)-   Component 3: 5 μL of kinase assay buffer-   Component 4: 5 μL of compound described herein (various    concentrations: 0, 0.1, 1, 10, 100 or 1000 nM or 1, 3, 10, 30, 100,    300 nM)-   Component 5: 5 μL of ³³P-ATP (5 M stock solution, 0.8 μCi; 20 μM    final concentration)

The assay was initiated by the addition of ³³P-ATP and the reactionmixture incubated at 30° C. for 15 minutes. After the incubation period,the assay was terminated by spotting 10 μL of the reaction mixture ontoMultiscreen phosphocellulose P81 plate. The Multiscreen phosphocelluloseP81 plate was washed 3 times for approximately 15 minutes each in a 1%phosphoric acid solution. The radioactivity on the P81 plate was countedin the presence of scintillation fluid in a Trilux scintillationcounter.

Blank controls were set up for each target kinase which included all theassay components except the addition of the appropriate substrate (whichwas replaced with equal volume of assay dilution buffer). The correctedactivity for each target kinase was determined by removing the blankcontrol value.

Compounds described herein, when tested in the above-describedradioisotope assay, demonstrated the ability to inhibit RSK2 as shownbelow in Table 2:

TABLE 2 Compound # RSK2 IC₅₀ 1 >10 μM 2 >10 μM 3 >10 μM 4 >10 μM 5 >10μM 6 >10 μM 7 >10 μM 8 >10 μM 9 >10 μM 10 >1 μM 11 1377 nM 12 >1 μM13 >1 μM 14 >1 μM 15 94 nM 16 23 nM 17 14 nM 18 12 nM 19 123 nM 20 124nM 25 18 nM

There are four RSK isoforms; RSK1, RSK2, RSK3 and RSK4. In someembodiments, the compounds described herein are active against all RSKisoforms. In some embodiments, the compounds described herein are activeagainst RSK1, RSK3 and RSK4 isoforms (Tables 3 and 4).

TABLE 3 RSK Isoform IC₅₀ of Compound #18 RSK1 2.0 nM RSK2  20 nM RSK31.7 nM RSK4 0.3 nM

TABLE 4 RSK Isoform IC₅₀ of Compound #15 RSK1 23.6 nM  RSK3 6.0 nM RSK48.0 nM

Biological Example 2 Solubility Assessments

Solubility is an important property for therapeutic drug candidates.Poor solubility can lead to low bioavailability resulting in suboptimaldrug delivery. It can also prevent the evaluation of test agents inanimals because the concentration(s) needed to achieve the desiredeffect cannot be achieved to poor solubility. For solubilityassessments, small molecules targeting RSK were compared. For theseassessments, 100 mM solutions of the compounds dissolved in DMSO werediluted in DMEM growth media (Life Technologies) supplemented with fetalbovine serum (FBS, Life Technologies) and 100 units/ml penicillin and100 units/ml streptomycin (Life Technologies) to make 20 mg/mlsolutions. Once diluted, the solutions were vortexed and examined forthe formation of precipitates. For compounds that remained in solution,the pH was determined using pH test strips (BDH Analytical Chemicals).For Compound 26, a 100 mM solution of the compound dissolved in DMSO wasdiluted in phosphate buffered saline (Life Technologies) to make a 20mg/ml solution. The stock of 20 mg/kg was chosen because this is theupper end of what would be required to dose mice for a range of studiesincluding MTD, PK, PD and efficacy. The pH of this solution wasdetermined to be 2, as previously described. Subsequently, 4M NaOH wasadded and the compound remained in solution at a pH equal to 9. At highconcentrations some RSK inhibitors were highly soluble while others werenot. Compound 0 is(R)—N-(1-benzyl-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide.Compound 0 was not soluble, whereas Compounds 18, 20, 21, 25 and 26 weresoluble under the same conditions (Table 5).

TABLE 5 Dissolving Diluting 20 mg/ml Compound Compound SolutionSolubility pH 0 DMSO DMEM Precipitate N/A 18 DMSO DMEM Soluble 9 20 DMSODMEM Soluble 8 21 DMSO DMEM Soluble 9 22 DMSO DMEM Precipitate N/A 23DMSO DMEM Precipitate N/A 24 DMSO DMEM Precipitate N/A 25 DMSO DMEMSoluble 2 26 DMSO PBS Soluble 2-9

Biological Example 3 Monolayer Growth Inhibition Assay

For cytotoxicity profiling of small molecule RSK2 kinase inhibitorsagainst breast cancer cell lines, compounds of the invention or vehiclecontrol (DMSO, Life Technologies) were diluted in media in 96 wellplates (Grenier Bio-One) in triplicate at final concentrations of0.1953125, 0.390625, 0.78125, 1.5625, 3.125, 6.25, 12.5, 25 and 50 M.1×10³ cells per well were seeded for a final volume of 200 μl per welland plates were incubated for 5 days at 37° C. in a humidified incubatorwith 5% CO₂. Following the incubation period, cell survival wasquantified by Alamar blue assay (Life Technologies). Briefly, media fromeach well was replaced with 100 μl of phosphate buffer saline (PBS, LifeTechnologies) and cells were incubated with 5% Alamar blue, whichincorporates a propriety redox indicator that changes colour in responseto metabolic activity, for up to 2 hours. During this period ofincubation, the absorbance at 570 nm and 600 nm was measured at varioustime points, depending on the cell line or sample. Percent survival wascalculated by comparing the absorbance ratio of the test well to thecontrol well multiplied by 100%, as indicated in the following formula:

${\% \mspace{14mu} {Survival}} = {\frac{( {{{Absorbance}\mspace{14mu} 570\mspace{14mu} {nm}} - {600\mspace{14mu} {nm}\mspace{14mu} ( {{Test}\mspace{14mu} {Well}} )}} }{( {{{Absorbance}\mspace{14mu} 570\mspace{14mu} {nm}} - {600\mspace{14mu} {nm}\mspace{14mu} ( {{Control}\mspace{14mu} {Well}} )}} } \times 100\%}$

Following, plates were prepared for crystal violet staining. To begin,100 μl of an 8% formaldehyde (Alfa Aesar) solution diluted in PBS wasadded to each well and plates were stored at 4° C. overnight. Next, theformaldehyde solution was discarded and the wells were washed with 200μl ultrapure water per well three times. Following, 50 μl of a 0.5%crystal violet solution (0.5% w/v crystal violet (Alfa Aesar), 25%methanol (VWR)) was added to each well and incubated at room temperaturefor 20 minutes. The crystal violet solution was discarded and wells werewashed with 200 μl ultrapure water per well three times. Next, 50 μl ofa 5% sodium dodecyl sulphate (SDS) (Alfa Aesar) was added to each welland the absorbance at 590 nm was measured. Similar to the Alamar blueassay, the percent survival was calculated by comparing the absorbanceratio of the test well to the control well multiplied by 100%.

A. Alamar Blue Assay Results:

Representative compounds described herein were tested in the Alamar blueassay against MDA-MB-231, MDA-MB-468, SUM149, SUM149-PTXR, MDA-MB-435,HCC1143, 4T1 and T47D breast cancer cell lines. The IC₅₀ values of thecompounds when tested for 5-days are provided below in Tables 6A and 6B.In all instances a single dose was given on day 1 of the experiment. Thecytotoxic ability of representative compounds against breast cancer celllines MDA-MB-231, MDA-MB-468, SUM149, and 4T1 are shown in FIGS. 1, 2,3, and 4, respectively.

TABLE 6A IC50 Values (μM)—Alamar Blue (5 Days) Type Cell Line 11 15 1617 18 19 TNBC MDA- >50 21.3 ± 5.4 8.7 ± 1.8 10.3 ± 0.7  6.3 ± 1.1 25.6 ±1.5 MB-231 MDA- >50 13.3 ± 4.1 2.7 ± 0.5 2.1 ± 1.1 4.1 ± 2.5 14.7 ± 4.1MB-468 SUM149 ⁺ 36.0 ± 12.8 11.7 ± 2.8  3.4 ± 1.8 8.3 ± 4.9 3.3 ± 1.915.8 ± 6.4 SUM149- 36.4 ± 11.9 9.2 ± 3.0 2.5 ± 0.4 4.2 ± 1.5 2.1 ± 0.314.1 ± 4.3 PTXR ⁺ HCC1143 >50 3.6 ± 2.7 7.0 ± 3.0 5.0 ± 1.7 4.2 ± 2.511.5 ± 3.6 HCC1937 ⁺ >50 9.7 ± 3.9 17.4 ± 3.0  6.8 ± 1.3 9.2 ± 1.1  16.6± 11.5 4T1 48.5 ± 2.6 8.8 ± 2.1 5.4 ± 0.9 3.8 ± 1.7 5.3 ± 2.5 20.6 ± 2.5ER/PR T47D 48.1 ± 3.3 7.8 ± 3.7 4.7 ± 1.7 5.7 ± 2.1 3.6 ± 1.7 13.5 ± 4.6HER2 JIMT-1 >50 8.3 ± 1.8 16.3 ± 1.0  12.6 ± 5.9  13.1 ± 6.4  37.3 ± 9.0Melanoma MDA-  24.6 ± 10.3 13.7 ± 3.4  0.9 ± 0.5 1.2 ± 1.0 0.7 ± 0.510.5 ± 2.2 MB-435 Prostate PC3 44.9 ± 8.8 11.5 ± 3.4  6.6 ± 2.3 6.0 ±3.2 5.5 ± 0.5 17.1 ± 8.7 All Range 24.6->50 3.6-21.3 0.9-17.4 1.2-12.60.7-13.1 10.5-37.3 ⁺ = BRCA Mutant

TABLE 6B IC50 Values (μM)—Alamar Blue (5 Days) Type Cell Line 21 22 2324 25 26 TNBC MDA- 14.7 ± 4.3  13.9 ± 3.5  7.8 ± 2.0 9.8 ± 3.1 3.9 ± 0.17.4 ± 1.7 MB-231 MDA- 6.5 ± 4.5 7.5 ± 2.1 9.7 ± 1.8 4.5 ± 2.3 3.0 ± 0.62.5 ± 0.7 MB-468 SUM149 ⁺ 2.7 ± 1.3 7.7 ± 4.6 3.0 ± 2.4 1.1 ± 0.9 10.4 ±3.5  9.8 ± 5.7 SUM149- 1.5 ± 0.8 7.8 ± 4.6 5.1 ± 4.0 3.4 ± 2.1 5.2 ± 4.28.8 ± 2.5 PTXR ⁺ HCC1143 5.4 ± 3.7 9.9 ± 1.0 9.7 ± 1.3 4.4 ± 1.9 5.1 ±0.3 9.6 ± 6.1 HCC1937 ⁺ 8.3 ± 2.4 12.6 ± 3.5  10.5 ± 1.0  9.2 ± 3.2 13.7± 3.8  5.6 ± 0.4 4T1 1.2 ± 0.3 4.5 ± 1.0 2.5 ± 0.8 0.5 ± 0.3 4.2 ± 1.26.2 ± 2.5 ER/PR T47D 8.0 ± 3.8 4.8 ± 0.9 6.0 ± 4.9 4.5 ± 4.1 8.9 ± 0.8 XHER2 JIMT-1 12.6 ± 6.4  17.1 ± 2.4  19.8 ± 7.1  12.3 ± 5.9  19.9 ± 6.5 15.5 ± 6.6  Melanoma MDA- 8.3 ± 5.3 6.8 ± 6.4 1.1 ± 0.7 5.6 ± 0.1 0.9 ±0.1 3.9 ± 1.3 MB-435 Prostate PC3 7.1 ± 0.9 9.2 ± 1.5 10.7 ± 1.1 12.0 ±4.5 8.5 ± 0.8 1.9 ± 0.8 All Range 1.2-14.7 4.5-17.1 1.1-19.8 0.5-12.30.9-19.9 1.9-15.5 ⁺ = BRCA Mutant

B. Crystal Violet Assay Results:

Representative compounds described herein were tested in the crystalviolet assay against MDA-MB-231, MDA-MB-468, SUM149, SUM149-PTXR,MDA-MB-435, HCC1143, 4T1 and T47D breast cancer cell lines. The IC₅₀values of the compounds when tested for 5-days are provided below inTables 7A and 7B. In all instances a single dose was given on day 1 ofthe experiment. The cytotoxic ability of representative compoundsagainst breast cancer cell lines MDA-MB-231, MDA-MB-468, SUM149, and 4T1are shown in FIGS. 5, 6, 7, and 8, respectively. Complete (100%) growthsuppression was achievable with several of the compounds in multipledifferent cell lines. This indicated that resistance to the RSKinhibitors was not observed.

TABLE 7A IC50 Values (μM)—Crystal Violet (5 Days) Type Cell Line 11 1516 17 18 19 TNBC MDA- 45.0 ± 8.7 21.0 ± 7.5  2.7 ± 1.3 5.1 ± 2.0 4.4 ±2.0 17.2 ± 1.9 MB-231 MDA- 37.3 ± 2.3 11.3 ± 0.7  1.9 ± 0.3 1.6 ± 0.72.3 ± 0.9  7.4 ± 1.0 MB-468 SUM149 ⁺  33.6 ± 14.5 9.9 ± 3.1 2.8 ± 0.95.3 ± 2.2 2.4 ± 0.7 11.1 ± 3.9 SUM149- 44.6 ± 3.9 8.8 ± 2.2 3.5 ± 1.25.2 ± 0.6 3.8 ± 0.7 13.0 ± 1.3 PTXR ⁺ HCC1143 >50 12.6 ± 3.4  5.0 ± 1.18.9 ± 3.2 2.4 ± 0.8 13.8 ± 4.3 HCC1937 ⁺ >50 12.0 ± 0.2  12.0 ± 5.3  7.3± 3.2 7.7 ± 3.5 19.9 ± 8.7 4T1 39.5 ± 9.4 6.9 ± 3.0 4.5 ± 0.8 2.0 ± 0.65.3 ± 1.1 15.8 ± 4.8 ER/PR T47D 30.1 ± 3.3 8.5 ± 0.7 3.8 ± 0.7 6.7 ± 1.62.2 ± 0.8  7.7 ± 1.5 HER2 JIMT-1 >50 11.2 ± 0.2  13.3 ± 2.4  7.4 ± 2.511.1 ± 0.5   34.0 ± 12.8 Mela- MDA- 17.9 ± 7.3 8.2 ± 2.5 1.2 ± 0.6 1.0 ±0.3 0.5 ± 0.2 10.3 ± 3.5 noma MB-435 Prostate PC3 45.6 ± 4.8 5.9 ± 1.43.7 ± 1.3 2.7 ± 1.2 2.9 ± 0.4 14.9 ± 6.6 All Range 17.9->50 5.9-21.01.2-13.3 1.0-8.9 0.5-11.1 7.4-34.0 ⁺ = BRCA Mutant

TABLE 7B IC50 Values (μM)—Crystal Violet (5 Days) Type Cell Line 21 2223 24 25 26 TNBC MDA- 9.1 ± 0.8 6.6 ± 2.1 3.6 ± 0.8 9.1 ± 1.3 4.2 ± 0.33.7 ± 1.8 MB-231 MDA- 4.6 ± 1.4 6.6 ± 2.3 7.2 ± 1.5 3.3 ± 1.3 2.0 ± 0.41.7 ± 0.2 MB-468 SUM149 ⁺ 2.4 ± 1.3 6.2 ± 4.8 2.1 ± 1.6 0.9 ± 0.3 4.1 ±1.5 6.5 ± 4.4 SUM149- 2.0 ± 0.2 8.0 ± 1.3 5.0 ± 2.4 4.5 ± 1.4 4.2 ± 0.66.5 ± 2.1 PTXR ⁺ HCC1143 9.5 ± 5.6 6.6 ± 3.1 7.3 ± 3.4 5.8 ± 2.6 4.4 ±2.7 7.3 ± 2.7 HCC1937 ⁺ 11.0 ± 1.0  9.9 ± 3.0 8.6 ± 3.0 5.8 ± 0.4 8.4 ±1.9 6.6 ± 1.6 4T1 1.1 ± 0.7 2.6 ± 1.5 1.8 ± 0.8 0.3 ± 0.1 2.9 ± 0.3 4.9± 1.1 ER/PR T47D 3.7 ± 2.7 4.3 ± 2.1 4.7 ± 4.9 2.7 ± 2.1 3.1 ± 0.1 XHER2 JIMT-1 11.3 ± 4.1  14.2 ± 5.1  15.0 ± 6.1  7.5 ± 2.2 15.2 ± 2.6 12.3 ± 3.2  Melanoma MDA- 4.8 ± 2.1 3.2 ± 1.3 1.1 ± 0.8 5.0 ± 3.6 0.5 ±0.3 1.6 ± 0.3 MB-435 Prostate PC3 4.3 ± 0.5 6.8 ± 1.8 6.8 ± 1.8 6.5 ±2.8 3.8 ± 0.4 1.5 ± 0.5 All Range 1.1-11.3 2.6-14.2 1.1-15.0 0.3-9.10.5-15.2 1.5-12.3 ⁺ = BRCA Mutant

Biological Example 4 Soft Agar Growth Inhibition Assay

Two agar (Alfa Aesar) solutions (0.8% w/v and 0.4% w/v) were prepared inultrapure water. The 0.8% agar solution was mixed in equal volumes with2× media previously prepared from powder (Life Technologies) followingthe manufacturer's instructions and filter sterilized. The 0.8% agar andmedia solution was added to 24 well plates (Mandel Scientific) at 500 μlper well. The plates were placed in a humidified incubator at 37° C.with 5% CO₂. Next, the 0.4% agar solution was mixed in equal volumeswith 2× media. Breast cancer cell lines were added to this solution toachieve a final concentration of 2×10⁴ cells per well and 500 μl wasadded to each well on top of the bottom agar and media layer. Following,a volume of 20 μl of compound or vehicle control (DMSO) was added todesignated wells in triplicate at the following final concentrations:0.078125, 0.15625, 0.3125, 0.625, 1.25, 2.5, 5, 10, and 20 μM. Theplates were returned to the incubator for 10-32 days, with a re-dosingof compounds or DMSO every 7 days. After 10-32 days, colonies werecounted in 3 different fields of view for each well. The counts for eachtreatment were averaged and the percent survival was calculated bycomparing the number of colonies in the test wells to the control wellsmultiplied by 100%.

Results:

Representative compounds described herein were tested in the soft agargrowth inhibition assay against the 4T1 breast cancer cell line. TheIC₅₀ values of the compounds when tested for 10 days are provided belowin Table 8A and when tested for 14-22 days are provided below in Table8B. The ability of representative compounds against the 4T1 breastcancer cell line to grow in soft agar is shown in FIG. 9A. Completegrowth suppression was achievable with 10 μM. The ability of Compound 25to similarly block growth in soft agar is shown in FIG. 9B usingMDA-MB-231, MDA-MB-468 or 4T1 cell lines. Complete growth suppressionwas achieved between 1.25-10 μM depending on the cell line.

TABLE 8A 4T1 + Compound #15, Compound #16 IC₅₀ Values (μM), 10 Days,Soft Agar Inhibitor IC₅₀ (μM) Compound #15 3.8 Compound #16 3.3

TABLE 8B Cell IC50 Values (μM)—Soft Agar (14-22 Days) Type Line Cpd 16Cpd 18 Cpd 21 Cpd 22 Cpd 23 Cpd 24 Cpd 25 Cpd 26 TNBC MDA- 0.2 ± 0.1 0.1± 0.0 2.0 ± 1.0 0.2 ± 0.1 0.3 ± 0.2 0.4 ± 0.2 0.2 ± 0.1 0.2 ± 0.1 MB-231MDA- 1.1 ± 0.3 0.3 ± 0.1 0.4 ± 0.1 6.9 ± 1.7 4.0 ± 0.8 2.5 ± 2.0 0.7 ±0.2 2.0 ± 0.2 MB-468 4T1 3.5 ± 0.3 2.5 ± 1.5 3.1 ± 0.6 3.8 ± 1.9 2.4 ±0.6 0.7 ± 0.3 4.1 ± 0.2 5.3 ± 1.3 All Range 0.2-3.5 0.1-2.5 0.4-3.10.2-6.9 0.3-4.0 0.4-2.5 0.2-4.1 0.2-5.3

Biological Example 5 RSK Inhibitors Suppress Cell Signalling Through theInhibition of Phosphorylated Y-Box Binding Protein-1 (P-YB-1)Immunoblotting Assessment of Cell Signaling Changes and the Induction ofCell Death

Generation of Cellular Extracts:

Following desired experimental conditions, breast cancer cell linesgrown and treated in 6 well plates or 100 mm culture dishes (GrenierBio-One) were placed on ice and the supernatant from each well wasremoved and the cells were washed in cold PBS. Following removal of PBS,cells were exposed to radioimmunoprecipitation assay (RIPA) buffer (50mM Tris-HCl (pH 8), 150 mM NaCl, 1% NP-40, 0.5% sodium deoxycholate,0.1% SDS; Fisher Scientific) supplemented with 1% phosphatase inhibitor(Fisher Scientific) and 1% protease inhibitor (Fisher Scientific) for 10minutes. Samples were transferred to eppendorf tubes, vortexed and thencentrifuged at 14 000 rpm for 10 minutes. Supernatants were collected aswhole cell lysates. For mouse tumour tissues, each sample was place in a35 mm culture dish with complete RIPA lysis buffer. The samples werediced in the buffer on ice with a sterile scalpel (VWR) and the bufferand tissue were transferred to an eppendorf tube. The samples were lefton ice for 10 minutes with periodic vortexing every 2 to 3 minutes. Thesamples were then transferred to a Qiashredder (Qiagen) and centrifugedat 14 000 rpm for 2 minutes. The flow through was transferred to a neweppendorf tube and the samples were centrifuged again at 14 000 rpm for5 minutes. Supernatants were collected as whole cell lysates.

Immunoblotting:

To begin, the protein content of the lysates was measured using theBicinchoninic Acid (BCA) Protein Assay Kit (Pierce), which included aprotein standard curve generated with bovine serum albumin. Appropriatevolumes of samples and loading buffer (50 mM Tris-HCl (pH 6.8), 2% SDS,10% glycerol, 1% β-mercaptoethanol, 12.5 mM EDTA, 0.02% bromophenolblue) were mixed, ensuring that equal amounts of protein were loaded.For the majority of experiments in this study, 30 μg of protein per wellwas loaded. Samples were then resolved on SDS-PAGE (polyacrylamide gelelectrophoresis) using various percentages of acrylamide gels (8%-12%),depending on the proteins of interest. SDS-PAGE was run in SDS runningbuffer (25 mM Tris, 192 mM glycine, 0.1% SDS) and then transferred tonitrocellulose membranes (Bio-Rad) in transfer buffer (48 mM Tris, 39 mMglycine, 20% (v/v) methanol) at 100 volts for 90 minutes at roomtemperature. Immunoblots were then blocked in 5% skim milk intris-buffered saline with 0.1% Tween-20 (TBS-T; 50 mM Tris-HCl, pH 7.5,150 mM NaCl, 0.1% (v/v) Tween-20 (Fisher Scientific)) for 1 to 2 hours.Immunoblots were then incubated with selected primary antibodies dilutedin TBS-T with 0.1% gelatin (Bio-Rad) and 0.05% sodium azide (Alfa Aesar)overnight. Following washes with TBT-T 4 times for 8 to 10 minutes,immunoblots were incubated with appropriate secondary antibodiesconjugated to horseradish peroxidise (Cell Signalling Technology)diluted in TBS-T plus 5% skim milk at a ratio of 1:5000 for 2 hours atroom temperature. After an additional round of washes in TBS-T,immunoblots were exposed to combined enhanced chemiluminescence (ECL)reagents (Fisher Scientific) for 1 minute and developed using ChemiDocMP Imaging System (Bio-Rad). For certain immunoblots, bands of proteinsof interest were scanned and band intensity ratios were determined bydensitometric analysis (ImageJ). Inhibitory or inactivation activity ofthe compounds of the invention was assessed by monitoring loss ofphosphorylated Y-box binding protein-1 (YB-1) at serine 102 (P-YB-1S102)(1:1000 Cell Signalling Technologies (CST) (FIGS. 10A, 10B, 11A, and11B). Treating MDA-MB-231 cells with a range (0.01, 0.1, 1, or 10 uM) ofCompound 18 or 25 led to a dose dependent loss of P-YB-1 after 24 hrs(FIG. 10A-B). B-actin was used as a loading control (1:5000 CST). Thebands were quantified using densitometry. Likewise, dosing MDA-MB-231cells with 0.01-1 uM of either Compound 16 or 18 for 96 hrs led to adose dependent loss of P-YB-1 (FIG. 11A-B). Using this methodology, theIC₅₀ values for P-YB-1 for Compounds 22, 23, 24, 25 and 26 weredetermined to be 24, 33, 16, 41 and 47 nM respectively. Total YB-1 wasused as a loading control (1:5000 Abcam). This was a direct measure ofRSK inactivation as YB-1 binds directly to the N-terminal kinase domain(NTKD) of RSK. To assess whether cells are actively undergoing celldeath, the activity of poly ADP ribose polymerase (PARP) (1:1000 CST)was also measured using the immunoblotting method.

Biological Example 6 RSK Inhibitors Induce Cell Death

The method for detecting PARP, P-YB-1, YB-1 and β-actin are describedabove (FIG. 12). MDA-MB-231, MDA-MB-468, SUM-149-PTX, HCC1143, HCC1937or 4T1 cells were treated with Compound 25 for 120 hrs at concentrationsof 2, 4 or 6 uM. The cells were harvested by scraping to collect allcells including those that had undergone apoptosis. Cells shown to haveundergone apoptosis based on PARP cleavage relative to the DMSO control.Further P-YB-1 was consistently reduced in all cell lines followingtreatment with Compound 25 relative to the DMSO controls. YB-1 andB-actin were included as loading controls. Total levels of PARP were notaffected at this timepoint.

Biological Example 7 RSK Inhibitors Combined with Standard of CareChemotherapy have a Synergistic Effect on Suppressing Tumor Cell Growth

For cytotoxicity profiling of combinations with compound of theinvention and the microtubule stabilizing agent paclitaxel againstbreast cancer cell lines, refer to Biological Example 2: MonolayerGrowth Inhibition Assay, with the following modifications. Dose responsestudies with paclitaxel as a single agent were carried out as describedwith paclitaxel at final concentrations of 0.078125, 0.15625, 0.3125,0.625, 1.25, 2.5, 5, 10, 20 μM in order to determine the suitable dosesfor further experiments. Combination treatments were performed bytreating breast cancer cell lines with single compounds of the inventionat final concentrations of 0.1953125, 0.390625, 0.78125, 1.5625, 3.125,6.25, 12.5, 25 and 50 M alongside combinations consisting of the sameconcentrations of the compounds and a single concentration of paclitaxeldetermined by the dose response studies (FIG. 13).

For RSK inhibitor Compound 18 represents an example of improved cellgrowth suppression when combined with a standard of care chemotherapy(eg. Paclitaxel). The IC50 of RSK inhibitors was lowered approximately10-fold by the addition of a sublethal dose of paclitaxel (PTX) (Table9). The combination index was calculated indicating there was synergyacross a range of concentrations (Table 10).

The RSK inhibitor Cpd 18 represents an example of improved cell growthsuppression when combined with a standard of care chemotherapy (eg.Paclitaxel). The IC50 of RSK inhibitors was lowered approximately10-fold by the addition of a sublethal dose of paclitaxel (PTX) (Table9). The combination index was calculated indicating there was synergyacross a range of concentrations (Table 10).

TABLE 9 Cell Growth (CV) Compound/Combination IC₅₀ Values (μM) Compound18 4.3 ± 1.0 Compound 18 + PTX (0.3 nM) 0.3 ± 0.1 MDA-MB-231 cellsexposed to compounds for 5 days MDA-MB-231 cells + 0.3 nM PTX: %Survival = 47.7%

TABLE 10 Compound 18 Coefficient of Drug (μM) Interaction (CDI) 0.2 1.60.4 1.2 0.8 0.8* 1.6 0.4* 3.1 0.2* 6.3 0.4* *Combination with paclitaxel(0.3 nM) considered synergistic MDA-MB-231 cells treated for 5 days

Biological Example 8 Immuno-Oncology

A key feature of cancer is low immunogenicity. This can occur by severalmechanisms that allow the cells to escape immune recognition. TreatingMDA-MB-231 and JIMT-1 cells with RSK inhibitors (ex. Compound 16 (2 or 4uM), Compound 18 (1, 2, or 4 uM)) elevated levels of HLA-DRA mRNA, buthad little effect on the mRNA expression of CIITA (FIGS. 14A, 14B).HLA-DRA is a member of MHC-II genes and CIITA is the master regulator ofMHC II transcription. Thus it was surprising that CIITA, which would beexpected to regulate MHC II gene expression, was not altered by RSKinhibition. Inhibiting RSK simultaneously inhibited CD274, the gene thatencodes program death receptor ligand 1 (PD-L1) (FIG. 14C, 14D).Compound 16 (2 or 4 uM) or Compound 18 1, 2 or 4 uM) reduced levels ofCD274 in MDA-MB-231 cells. Likewise, Compound 18 at varyingconcentrations (1-20 uM) also inhibited CD274 in JIMT-1 cells. HLA-DRAis important for immune recognition while PD-L1 is involved in immunecheckpoints.

Biological Example 9 RSK Inhibitors have Favourable PharmacodynamicsProperties, Ex. Delivery to Tumors

Due to its poor or nonexistent solubility, as discussed above atBiological Example 2, Compound 0 could not be evaluated forpharmacodynamics. Conversely, Compound 25 had superior solubility forsystemic delivery in mice (Table 5).

MDA-MB-231 cells were injected into the mammary fat pad of nu/nu miceand tumors were established. Once the tumors reached 50-100 mm³ the micewere randomized into two groups, vehicle control or Compound 25 treated.The mice received Compound 25 100 mg/kg BID PO for three days. Cellsignalling was evaluated by immunoblotting. The levels of Cpd 25 in theplasma and tumors was determined by LC/MS (FIG. 15). Compound 25 reducedcell signaling through loss of P-YB-1 in 3/3 tumors. YB-1 and B-Actinwere included as loading controls. Tumor and plasma levels of Compound25 were on average 7.1 and 35.1 uM respectively. The ratio between thetumor and plasma indicates excellent tumor uptake (20%). Similarly,tumors were also obtained from mice treated for 21 days with Compound 25as described above and cell signalling was assessed by immunoblotting(FIG. 16A). Compound 25 consistently reduced P-YB-1 signaling in 9/9tumors relative to the vehicle control treated tumors. YB-1 and B-actinwere included as internal loading controls. The loss of P-YB-1 signalingwas quantified using Image J for animals 4, 6, 8, 9, and 10 (FIG. 16B).Levels of Compound 25 were also quantified in the tumors taken from micetreated for 21 days, the average concentration in the tumors was 7.7 uM.The tumors from mice treated for either 3 or 21 days were harvested 30minutes after the last oral dosing of Compound 25. In summary, Compound25 exhibited excellent tumor uptake and reduced P-YB-1 signaling in12/12 (n=3 (treated for 3 days), n=9 (treated for 21 days) tumorsrelative to the vehicle control treated tumors, whereas Compound 0 couldnot be dosed in vivo due to its poor solubility.

Biological Example 10 Colony Forming Unit Hematopoietic Stem Cell Assay

The hematopoietic colony forming cell assay was conducted based on aprotocol outlined by StemCell Technologies. To begin, severalconcentrations of the compounds of the invention and DMSO (0.625, 1.25,2.5, 5, 10, 20 μM) were added to separate tubes of MethoCult (StemCellTechnologies), a methylcellulose matrix containing recombinant humancytokines stem cell factor (rh SCF), granulocyte macrophagecolony-stimulating factor (rh GM-CSF), interleukin-3 (rh L-3),granulocyte colony stimulating factor (rh G-CSF) and erythropoietin (rhEPO). Following the addition of CD34⁺ cells isolated from human cordblood or peripheral blood (StemCell Technologies) at a finalconcentration of 5×10² cells per dish, the tubes were vortexed andallowed to stand for 5 minutes at room temperature. Next, the MethoCultmixtures were dispensed into 35 mm dishes (Corning Incorporated) throughblunt end needles (StemCell Technologies) and 5 ml syringes (BDBiosciences) at a volume of 1.1 ml per dish. The medium was evenlydistributed across the surface of each dish by gentle tilting androtation. The dishes were then placed in a 100 mm culture dish (GrenierBio-One) containing additional 35 mm dishes with sterile water tomaintain humidity. The culture dish was then placed at 37° C. in ahumidified incubator containing 5% CO₂ for 13 days. The number ofmyeloid and erythroid derived colonies in both the treated and controldishes were counted and compared.

RSK inhibitors do not inhibit the differentiation of normal humanhematopoetic stem cell precursor cells as compared to cancer cells. Bycontrast, Compound #15 inhibited 50% of cancer cell growth with 3.8 uM,whereas 100% of the cells were viable in the HSC assay. A representativecompound described herein, i.e., Compound #15, when tested in thisassay, demonstrated the following IC₅₀, as shown in Table 11:

TABLE 11 IC₅₀ Values (μM) - 14 days, CFU Assay Cells Type Compound #15CD34+ HSC 23.8

A therapeutic window refers to the range of dosage of a drug or of itsconcentration in a bodily system that provides safe effective therapy.Hematopoietic stem cell differentiation from human primary bone marrowstems cells was used to assess therapeutic safety and to determine andcompare safety windows of several compounds described herein, namelyCompounds 0, 16, 18, and 25. Compared to Compound 0 and Taxol, Compounds16, 18 and 25 have greater therapeutic windows, as indicated by theratio IC₅₀ values of the compounds against CD34⁺ cells and MDA-MB-231cells (Table 12, FIG. 17). The values were compared to the concentrationneeded to block growth in soft agar (SA).

TABLE 12 CD34⁺ (PB), MDA-MB-231 + Compounds, Taxol - IC₅₀ ValuesCompound CD34⁺ (PB) MDA-MB-231 Therapeutic Window 0  10.0 μM 0.2 μM (SA) 50X 16 >20.0 μM 0.2 μM (SA) >100X 18  16.3 μM 0.1 μM (SA)  163X25 >20.0 μM 0.2 μM (SA) >100X Taxol  9.7 nM 1.4 nM (SA)    6.9X

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, PCT published patent applications, foreign patents,foreign patent applications and non-patent publications referred to inthis specification are incorporated herein by reference in theirentirety.

Although the foregoing invention has been described in some detail tofacilitate understanding, it will be apparent that certain changes andmodifications may be practiced within the scope of the appended claims.Accordingly, the described embodiments are to be considered asillustrative and not restrictive, and the invention is not to be limitedto the details given herein, but may be modified within the scope andequivalents of the appended claims.

What is claimed is:
 1. A compound of formula (I):

wherein: n is 1 or 2; A is —N═ or —C(R³)═; B is —O—, —N(R⁴)—, or—S(O)_(t) (where t is 0, 1 or 2)-; E is —N═ or —C(R³)═; R¹ isR⁵—C(O)N(R⁶)—, R⁷—N(R⁶)C(O)—, R⁵—N(R⁶)C(O)N(R⁶)—, orR⁵—N(R⁶)C(═NR⁶)N(R⁶)—; each R² is independently hydrogen, alkyl, halo,haloalkyl, optionally substituted aryl, optionally substituted aralkyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl oroptionally substituted heteroarylalkyl; or two R², together with theadjacent carbons to which they are attached, form a fused optionallysubstituted 6-membered N-heterocyclyl; each R³ is independentlyhydrogen, alkyl, haloalkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl or optionally substituted heteroarylalkyl; R⁴ is hydrogen,alkyl, haloalkyl, optionally substituted aryl or optionally substitutedaralkyl; or R⁴, together with the nitrogen to which it is attached, anda R², together with the adjacent carbon to which it is attached,together form a fused 6-membered N-heterocyclyl of the followingstructure:

where

indicates the point of fusion and R^(4a), R^(4b), R^(4c), and R^(4d) areeach independently hydrogen, alkyl, halo or haloalkyl or R^(4a) andR^(4b), together with the carbon to which they are both attached, form acycloalkyl or R^(4c) and R^(4d), together with the carbon to which theyare both attached, form a cycloalkyl, and the remaining R², if present,is selected from hydrogen, alkyl, halo or haloalkyl; R⁵ is optionallysubstituted aryl or optionally substituted N-heteroaryl; each R⁶ isindependently hydrogen, alkyl, haloalkyl, optionally substituted aryl oroptionally substituted aralkyl; R⁷ is optionally substituted aryl oroptionally substituted N-heteroaryl when E is —N═; or R⁷ is a monocyclicN-heteroaryl substituted with an optionally substituted aralkyl when Eis —C(R³)═ and one R² is halo, haloalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl or optionally substituted heteroarylalkyl; or R⁷is a monocyclic N-heteroaryl substituted with an optionally substitutedaralkyl when E is —C(R³)═ and one of R^(4a) and R^(4b) is not methyl andthe other is not hydrogen; or R⁷ is a monocyclic N-heteroarylsubstituted with an optionally substituted aralkyl when E is —C(R³)═ andtwo of R^(4a), R^(4b), R^(4c), and R^(4d) on adjacent carbons are notboth methyl and the other two are not both hydrogen; or R⁷ is amonocyclic N-heteroaryl substituted with an optionally substitutedaralkyl when E is —C(R³)═ and R^(4a) and R^(4b), together with thecarbon to which they are both attached, form a cycloalkyl or R^(4c) andR^(4d), together with the carbon to which they are both attached, form acycloalkyl; or R⁷ is a monocyclic N-heteroaryl substituted by an aralkylsubstituted with halo, haloalkyl, —CN, —NO₂, —N(R⁶)₂, —N(R⁶)C(O)OR⁶,—C(O)R⁶, —C(O)OR⁶ or —C(O)N(R⁶)₂ when E is —C(R³)═ and R^(4a) is methyland R^(4b), R^(4c), and R^(4d) are each hydrogen or when E is —C(R³)═and R^(4a) and R^(4c) are each methyl and R^(4b) and R^(4d) are eachhydrogen; or R⁷ is a monocyclic N-heteroaryl substituted with optionallysubstituted N-heterocyclylalkyl when E is —C(R³)═; as an individualstereoisomer, enantiomer or tautomer thereof or a mixture thereof; or apharmaceutically acceptable salt, solvate, or prodrug thereof.
 2. Thecompound of claim 1 having the formula (Ia):

wherein: n is 1 or 2; A is —N═ or —C(R³)═; B is —O—, —N(R⁴)—, or—S(O)_(t) (where t is 0, 1 or 2)-; E is —N═ or —C(R³)═; each R² isindependently hydrogen, alkyl, halo, haloalkyl, optionally substitutedaryl, optionally substituted aralkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl or optionally substituted heteroarylalkyl; or twoR², together with the adjacent carbons to which they are attached, forma fused optionally substituted 6-membered N-heterocyclyl; each R³ isindependently hydrogen, alkyl, haloalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl or optionally substituted heteroarylalkyl; R⁴ ishydrogen, alkyl, haloalkyl, optionally substituted aryl or optionallysubstituted aralkyl; or R⁴, together with the nitrogen to which it isattached, and a R², together with the adjacent carbon to which it isattached, together form a fused 6-membered N-heterocyclyl of thefollowing structure:

where

indicates the point of fusion and R^(4a), R^(4b), R^(4c), and R^(4d) areeach independently hydrogen, alkyl, halo or haloalkyl or R^(4a) andR^(4b), together with the carbon to which they are both attached, form acycloalkyl or R^(4c) and R^(4d), together with the carbon to which theyare both attached, form a cycloalkyl, and the remaining R², if present,is selected from hydrogen, alkyl, halo or haloalkyl; R⁵ is optionallysubstituted aryl or optionally substituted N-heteroaryl; and R⁶ ishydrogen, alkyl, haloalkyl, optionally substituted aryl or optionallysubstituted aralkyl.
 3. The compound of claim 2 having the formula(Ia1):

wherein: n is 1 or 2; B is —O—, —N(R⁴)—, or —S(O)_(t) (where t is 0, 1or 2)-; E is —N═ or —C(R³)═; each R² is independently hydrogen, alkyl,halo, haloalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl oroptionally substituted heteroarylalkyl; or two R², together with theadjacent carbons to which they are attached, form a fused optionallysubstituted 6-membered N-heterocyclyl; each R³ is independentlyhydrogen, alkyl, haloalkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl or optionally substituted heteroarylalkyl; R⁴ is hydrogen,alkyl, haloalkyl, optionally substituted aryl or optionally substitutedaralkyl; or R⁴, together with the nitrogen to which it is attached, anda R², together with the adjacent carbon to which it is attached,together form a fused 6-membered N-heterocyclyl of the followingstructure:

where

indicates the point of fusion and R^(4a), R^(4b), R^(4c), and R^(4d) areeach independently hydrogen, alkyl, halo or haloalkyl or R^(4a) andR^(4b), together with the carbon to which they are both attached, form acycloalkyl or R^(4c) and R^(4d), together with the carbon to which theyare both attached, form a cycloalkyl, and the remaining R², if present,is selected from hydrogen, alkyl, halo or haloalkyl; R⁵ is optionallysubstituted aryl or optionally substituted N-heteroaryl; and R⁶ ishydrogen, alkyl, haloalkyl, optionally substituted aryl or optionallysubstituted aralkyl.
 4. The compound of claim 3 wherein: n is 1 or 2; Bis —N(R⁴)—; E is —N═ or —C(R³)═; each R² is independently hydrogen,halo, alkyl, haloalkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl or optionally substituted heteroarylalkyl; or two R²,together with the adjacent carbons to which they are attached, form afused optionally substituted 6-membered N-heterocyclyl; each R³ isindependently hydrogen, alkyl, haloalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl or optionally substituted heteroarylalkyl; R⁴ ishydrogen, alkyl, haloalkyl, optionally substituted aryl or optionallysubstituted aralkyl; or R⁴, together with the nitrogen to which it isattached, and a R², together with the adjacent carbon to which it isattached, together form a fused 6-membered N-heterocyclyl of thefollowing structure:

where

indicates the point of fusion and R^(4a), R^(4b), R^(4c), and R^(4d) areeach independently hydrogen, alkyl, halo or haloalkyl or R^(4a) andR^(4b), together with the carbon to which they are both attached, form acycloalkyl or R^(4c) and R^(4d), together with the carbon to which theyare both attached, form a cycloalkyl, and the remaining R², if present,is selected from hydrogen, alkyl, halo or haloalkyl; R⁵ is optionallysubstituted aryl or optionally substituted N-heteroaryl; and R⁶ ishydrogen, alkyl, haloalkyl, optionally substituted aryl or optionallysubstituted aralkyl.
 5. The compound of claim 4 selected from:1-benzyl-N-(3-(morpholinomethyl)-1H-indol-5-yl)-1H-pyrazole-4-carboxamidehydrochloride;1-benzyl-N-(3-(morpholinomethyl)-1H-indol-6-yl)-1H-pyrazole-4-carboxamidehydrochloride;1-benzyl-N-(3-((4-methylpiperazin-1-yl)methyl)-1H-indol-5-yl)-1H-pyrazole-4-carboxamidedihydrochloride;1-benzyl-N-(3-((4-methylpiperazin-1-yl)methyl)-1H-indol-6-yl)-1H-pyrazole-4-carboxamidedihydrochloride;1-benzyl-N-(2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-8-yl)-1H-pyrazole-4-carboxamidehydrochloride;(S)-1-benzyl-N-(6-methyl-9-oxo-6,7,8,9-tetrahydropyrido[2′,3′:4,5]pyrrolo[1,2-a]pyrazin-3-yl)-1H-pyrazole-4-carboxamide;and(S)-1-benzyl-N-(6-methyl-9-oxo-6,7,8,9-tetrahydropyrido[2′,3′:4,5]pyrrolo[1,2-a]pyrazin-2-yl)-1H-pyrazole-4-carboxamide.6. The compound of claim 3 wherein: n is 1 or 2; B is —O—; E is —N═ or—C(R³)═; each R² is independently hydrogen, alkyl, halo, haloalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl or optionallysubstituted heteroarylalkyl; or two R², together with the adjacentcarbons to which they are attached, form a fused optionally substituted6-membered N-heterocyclyl; each R³ is independently hydrogen, alkyl,haloalkyl, optionally substituted aryl, optionally substituted aralkyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl oroptionally substituted heteroarylalkyl; R⁵ is optionally substitutedaryl or optionally substituted N-heteroaryl; and R⁶ is hydrogen, alkyl,haloalkyl, optionally substituted aryl or optionally substitutedaralkyl.
 7. The compound of claim 6 selected from:1-benzyl-N-(3-(morpholinomethyl)benzofuran-6-yl)-1H-pyrazole-4-carboxamidehydrochloride;1-benzyl-N-(3-(morpholinomethyl)benzofuran-5-yl)-1H-pyrazole-4-carboxamidehydrochloride;1-benzyl-N-(3-(piperazin-1-ylmethyl)benzofuran-5-yl)-1H-pyrazole-4-carboxamidedihydrochloride;1-benzyl-N-(3-(piperazin-1-ylmethyl)benzofuran-6-yl)-1H-pyrazole-4-carboxamidedihydrochloride; and1-benzyl-N-(2-methyl-1,2,3,4-tetrahydrobenzofuro[3,2-c]pyridin-8-yl)-1H-pyrazole-4-carboxamidehydrochloride.
 8. The compound of claim 3 wherein: n is 1 or 2; B is—S(O)_(t) (where t is 0, 1 or 2)-; E is —N═ or —C(R³)═; each R² isindependently hydrogen, alkyl, halo, haloalkyl, optionally substitutedaryl, optionally substituted aralkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl or optionally substituted heteroarylalkyl; or twoR², together with the adjacent carbons to which they are attached, forma fused optionally substituted 6-membered N-heterocyclyl; each R³ isindependently hydrogen, alkyl, haloalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl or optionally substituted heteroarylalkyl; R⁵ isoptionally substituted aryl or optionally substituted N-heteroaryl; andR⁶ is hydrogen, alkyl, haloalkyl, optionally substituted aryl oroptionally substituted aralkyl.
 9. The compound of claim 8 selectedfrom:1-benzyl-N-(3-(morpholinomethyl)benzo[b]thiophen-5-yl)-1H-pyrazole-4-carboxamidehydrochloride; and1-benzyl-N-(3-(piperazin-1-ylmethyl)benzo[b]thiophen-5-yl)-1H-pyrazole-4-carboxamidedihydrochloride.
 10. The compound of claim 2 having the formula (Ia2):

wherein: n is 1 or 2; B is —O—, —N(R⁴)—, or —S(O)_(t) (where t is 0, 1or 2)-; E is —N═ or —C(R³)═; each R² is independently hydrogen, alkyl,halo, haloalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl oroptionally substituted heteroarylalkyl; or two R², together with theadjacent carbons to which they are attached, form a fused optionallysubstituted 6-membered N-heterocyclyl; R³ is hydrogen, alkyl, haloalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl or optionallysubstituted heteroarylalkyl; R⁴ is hydrogen, alkyl, haloalkyl,optionally substituted aryl or optionally substituted aralkyl; or R⁴,together with the nitrogen to which it is attached, and a R², togetherwith the adjacent carbon to which it is attached, together form a fused6-membered N-heterocyclyl of the following structure:

where

indicates the point of fusion and R^(4a), R^(4b), R^(4c), and R^(4d) areeach independently hydrogen, alkyl, halo or haloalkyl or R^(4a) andR^(4b), together with the carbon to which they are both attached, form acycloalkyl or R^(4c) and R^(4d), together with the carbon to which theyare both attached, form a cycloalkyl, and the remaining R², if present,is selected from hydrogen, alkyl, halo or haloalkyl; R⁵ is optionallysubstituted aryl or optionally substituted N-heteroaryl; and R⁶ ishydrogen, alkyl, haloalkyl, optionally substituted aryl or optionallysubstituted aralkyl.
 11. The compound of claim 10 wherein: n is 1 or 2;B is —N(R⁴)—; E is —N═ or —C(R³)═; each R² is independently hydrogen,alkyl, halo, haloalkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl or optionally substituted heteroarylalkyl; or two R²,together with the adjacent carbons to which they are attached, form afused optionally substituted 6-membered N-heterocyclyl; R³ is hydrogen,alkyl, haloalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl oroptionally substituted heteroarylalkyl; R⁴ is hydrogen, alkyl,haloalkyl, optionally substituted aryl or optionally substitutedaralkyl; or R⁴, together with the nitrogen to which it is attached, anda R², together with the adjacent carbon to which it is attached,together form a fused 6-membered N-heterocyclyl of the followingstructure:

where

indicates the point of fusion and R^(4a), R^(4b), R^(4c), and R^(4d) areeach independently hydrogen, alkyl, halo or haloalkyl or R^(4a) andR^(4b), together with the carbon to which they are both attached, form acycloalkyl or R^(4c) and R^(4d), together with the carbon to which theyare both attached, form a cycloalkyl, and the remaining R², if present,is selected from hydrogen, alkyl, halo or haloalkyl; R⁵ is optionallysubstituted aryl or optionally substituted N-heteroaryl; and R⁶ ishydrogen, alkyl, haloalkyl, optionally substituted aryl or optionallysubstituted aralkyl.
 12. The compound of claim 11 selected from:(R)-1-benzyl-N-(4-methyl-1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indol-7-yl)-1H-pyrazole-4-carboxamide;1-benzyl-N-(1-oxo-1,2,3,4-tetrahydropyrazino[1,2-a]indol-7-yl)-1H-pyrazole-4-carboxamide;1-benzyl-N-((9R)-9-methyl-6-oxo-5,5a,6,7,8,9-hexahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-2-yl)-1H-pyrazole-4-carboxamide;and(R)-1-(3-aminobenzyl)-N-(9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-2-yl)-1H-pyrazole-4-carboxamide.13. The compound of claim 10 wherein: n is 1 or 2; B is —O—; E is —N═ or—C(R³)═; each R² is independently hydrogen, alkyl, halo, haloalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl or optionallysubstituted heteroarylalkyl; or two R², together with the adjacentcarbons to which they are attached, form a fused optionally substituted6-membered N-heterocyclyl; R³ is hydrogen, alkyl, haloalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heteroaryl or optionally substitutedheteroarylalkyl; R⁵ is optionally substituted aryl or optionallysubstituted N-heteroaryl; and R⁶ is hydrogen, alkyl, haloalkyl,optionally substituted aryl or optionally substituted aralkyl.
 14. Thecompound of claim 10 wherein: n is 1 or 2; B is —S(O)_(t) (where t is 0,1 or 2)-; E is —N═ or —C(R³)═; each R² is independently hydrogen, alkyl,halo, haloalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl oroptionally substituted heteroarylalkyl; or two R², together with theadjacent carbons to which they are attached, form a fused optionallysubstituted 6-membered N-heterocyclyl; R³ is hydrogen, alkyl, haloalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl or optionallysubstituted heteroarylalkyl; R⁵ is optionally substituted aryl oroptionally substituted N-heteroaryl; and R⁶ is hydrogen, alkyl,haloalkyl, optionally substituted aryl or optionally substitutedaralkyl.
 15. The compound of claim 1 having the formula (Ib):

wherein: n is 1 or 2; A is —N═ or —C(R³)═; B is —O—, —N(R⁴)—, or—S(O)_(t) (where t is 0, 1 or 2)-; E is —N═ or —C(R³)═; each R² isindependently hydrogen, alkyl, halo, haloalkyl, optionally substitutedaryl, optionally substituted aralkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl or optionally substituted heteroarylalkyl; or twoR², together with the adjacent carbons to which they are attached, forma fused optionally substituted 6-membered N-heterocyclyl; each R³ isindependently hydrogen, alkyl, haloalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl or optionally substituted heteroarylalkyl; R⁴ ishydrogen, alkyl, haloalkyl, optionally substituted aryl or optionallysubstituted aralkyl; or R⁴, together with the nitrogen to which it isattached, and a R², together with the adjacent carbon to which it isattached, together form a fused 6-membered N-heterocyclyl of thefollowing structure:

where

indicates the point of fusion and R^(4a), R^(4b), R^(4c), and R^(4d) areeach independently hydrogen, alkyl, halo or haloalkyl or R^(4a) andR^(4b), together with the carbon to which they are both attached, form acycloalkyl or R^(4c) and R^(4d), together with the carbon to which theyare both attached, form a cycloalkyl, and the remaining R², if present,is selected from hydrogen, alkyl, halo or haloalkyl; each R⁶ isindependently hydrogen, alkyl, haloalkyl, optionally substituted aryl oroptionally substituted aralkyl; and R⁷ is optionally substituted aryl oroptionally substituted N-heteroaryl when E is —N═; or R⁷ is a monocyclicN-heteroaryl substituted with an optionally substituted aralkyl when Eis —C(R³)═ and one R² is halo, haloalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl or optionally substituted heteroarylalkyl; or R⁷is a monocyclic N-heteroaryl substituted with an optionally substitutedaralkyl when E is —C(R³)═ and one of R^(4a) and R^(4b) is not methyl andthe other is not hydrogen; or R⁷ is a monocyclic N-heteroarylsubstituted with an optionally substituted aralkyl when E is —C(R³)═ andtwo of R^(4a), R^(4b), R^(4c), and R^(4d) on adjacent carbons are notboth methyl and the other two are not both hydrogen; or R⁷ is amonocyclic N-heteroaryl substituted with an optionally substitutedaralkyl when E is —C(R³)═ and R^(4a) and R^(4b), together with thecarbon to which they are both attached, form a cycloalkyl or R^(4c) andR^(4d), together with the carbon to which they are both attached, form acycloalkyl; or R⁷ is a monocyclic N-heteroaryl substituted by an aralkylsubstituted with halo, haloalkyl, —CN, —NO₂, —N(R⁶)₂, —N(R⁶)C(O)OR⁶,—C(O)R⁶, —C(O)OR⁶ or —C(O)N(R⁶)₂ when E is —C(R³)═ and R^(4a) is methyland R^(4b), R^(4c), and R^(4d) are each hydrogen or when E is —C(R³)═and R^(4a) and R^(4c) are each methyl and R^(4b) and R^(4d) are eachhydrogen; or R⁷ is a monocyclic N-heteroaryl substituted with optionallysubstituted N-heterocyclylalkyl when E is —C(R³)═.
 16. The compound ofclaim 15 having the formula (Ib1):

wherein: n is 1 or 2; B is —O—, —N(R⁴)—, or —S(O)_(t) (where t is 0, 1or 2)-; E is —N═ or —C(R³)═; each R² is independently hydrogen, alkyl,halo, haloalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl oroptionally substituted heteroarylalkyl; or two R², together with theadjacent carbons to which they are attached, form a fused optionallysubstituted 6-membered N-heterocyclyl; each R³ is independentlyhydrogen, alkyl, haloalkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl or optionally substituted heteroarylalkyl; R⁴ is hydrogen,alkyl, haloalkyl, optionally substituted aryl or optionally substitutedaralkyl; or R⁴, together with the nitrogen to which it is attached, anda R², together with the adjacent carbon to which it is attached,together form a fused 6-membered N-heterocyclyl of the followingstructure:

where

indicates the point of fusion and R^(4a), R^(4b), R^(4c), and R^(4d) areeach independently hydrogen, alkyl, halo or haloalkyl or R^(4a) andR^(4b), together with the carbon to which they are both attached, form acycloalkyl or R^(4c) and R^(4d), together with the carbon to which theyare both attached, form a cycloalkyl, and the remaining R², if present,is selected from hydrogen, alkyl, halo or haloalkyl; each R⁶ isindependently hydrogen, alkyl, haloalkyl, optionally substituted aryl oroptionally substituted aralkyl; and R⁷ is optionally substituted aryl oroptionally substituted N-heteroaryl when E is —N═; or R⁷ is a monocyclicN-heteroaryl substituted with an optionally substituted aralkyl when Eis —C(R³)═ and one R² is halo, haloalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl or optionally substituted heteroarylalkyl; or R⁷is a monocyclic N-heteroaryl substituted with an optionally substitutedaralkyl when E is —C(R³)═ and one of R^(4a) and R^(4b) is not methyl andthe other is not hydrogen; or R⁷ is a monocyclic N-heteroarylsubstituted with an optionally substituted aralkyl when E is —C(R³)═ andtwo of R^(4a), R^(4b), R^(4c), and R^(4d) on adjacent carbons are notboth methyl and the other two are not both hydrogen; or R⁷ is amonocyclic N-heteroaryl substituted with an optionally substitutedaralkyl when E is —C(R³)═ and R^(4a) and R^(4b), together with thecarbon to which they are both attached, form a cycloalkyl or R^(4c) andR^(4d), together with the carbon to which they are both attached, form acycloalkyl; or R⁷ is a monocyclic N-heteroaryl substituted by an aralkylsubstituted with halo, haloalkyl, —CN, —NO₂, —N(R⁶)₂, —N(R⁶)C(O)OR⁶,—C(O)R⁶, —C(O)OR⁶ or —C(O)N(R⁶)₂ when E is —C(R³)═ and R^(4a) is methyland R^(4b), R^(4c), and R^(4d) are each hydrogen or when E is —C(R³)═and R^(4a) and R^(4c) are each methyl and R^(4b) and R^(4d) are eachhydrogen; or R⁷ is a monocyclic N-heteroaryl substituted with optionallysubstituted N-heterocyclylalkyl when E is —C(R³)═.
 17. The compound ofclaim 16 wherein: n is 1 or 2; B is —N(R⁴)—; E is —N═ or —C(R³)═; eachR² is independently hydrogen, alkyl, halo, haloalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heteroaryl or optionally substitutedheteroarylalkyl; or two R², together with the adjacent carbons to whichthey are attached, form a fused optionally substituted 6-memberedN-heterocyclyl; each R³ is independently hydrogen, alkyl, haloalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl or optionallysubstituted heteroarylalkyl; R⁴ is hydrogen, alkyl, haloalkyl,optionally substituted aryl or optionally substituted aralkyl; R⁴ ishydrogen, alkyl, haloalkyl, optionally substituted aryl or optionallysubstituted aralkyl; or R⁴, together with the nitrogen to which it isattached, and a R², together with the adjacent carbon to which it isattached, together form a fused 6-membered N-heterocyclyl of thefollowing structure:

where

indicates the point of fusion and R^(4a), R^(4b), R^(4c), and R^(4d) areeach independently hydrogen, alkyl, halo or haloalkyl or R^(4a) andR^(4b), together with the carbon to which they are both attached, form acycloalkyl or R^(4c) and R^(4d), together with the carbon to which theyare both attached, form a cycloalkyl, and the remaining R², if present,is selected from hydrogen, alkyl, halo or haloalkyl; R⁷ is optionallysubstituted aryl or optionally substituted N-heteroaryl when E is —N═;or R⁷ is a monocyclic N-heteroaryl substituted with an optionallysubstituted aralkyl when E is —C(R³)═ and one R² is halo, haloalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl or optionallysubstituted heteroarylalkyl; or R⁷ is a monocyclic N-heteroarylsubstituted with an optionally substituted aralkyl when E is —C(R³)═ andone of R^(4a) and R^(4b) is not methyl and the other is not hydrogen; orR⁷ is a monocyclic N-heteroaryl substituted with an optionallysubstituted aralkyl when E is —C(R³)═ and two of R^(4a), R^(4b), R^(4c),and R^(4d) on adjacent carbons are not both methyl and the other two arenot both hydrogen; or R⁷ is a monocyclic N-heteroaryl substituted withan optionally substituted aralkyl when E is —C(R³)═ and R^(4a) andR^(4b), together with the carbon to which they are both attached, form acycloalkyl or R^(4c) and R^(4d), together with the carbon to which theyare both attached, form a cycloalkyl; or R⁷ is a monocyclic N-heteroarylsubstituted by an aralkyl substituted with halo, haloalkyl, —CN, —NO₂,—N(R⁶)₂, —N(R⁶)C(O)OR⁶, —C(O)R⁶, —C(O)OR⁶ or —C(O)N(R⁶)₂ when E is—C(R³)═ and R^(4a) is methyl and R^(4b), R^(4c), and R^(4d) are eachhydrogen or when E is —C(R³)═ and R^(4a) and R^(4c) are each methyl andR^(4b) and R^(4d) are each hydrogen; or R⁷ is a monocyclic N-heteroarylsubstituted with optionally substituted N-heterocyclylalkyl when E is—C(R³)═.
 18. The compound of claim 17 selected from:(S)—N-(1-benzyl-1H-pyrazol-4-yl)-6-methyl-9-oxo-6,7,8,9-tetrahydropyrido[2′,3′:4,5]pyrrolo[1,2-a]pyrazine-3-carboxamide;and(S)—N-(1-benzyl-1H-pyrazol-4-yl)-6-methyl-9-oxo-6,7,8,9-tetrahydropyrido[2′,3′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide.19. The compound of claim 16 wherein: n is 1 or 2; B is —O—; E is —N═ or—C(R³)═; each R² is independently hydrogen, alkyl, halo, haloalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl or optionallysubstituted heteroarylalkyl; or two R², together with the adjacentcarbons to which they are attached, form a fused optionally substituted6-membered N-heterocyclyl; each R³ is independently hydrogen, alkyl,haloalkyl, optionally substituted aryl, optionally substituted aralkyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl oroptionally substituted heteroarylalkyl; each R⁶ is independentlyhydrogen, alkyl, haloalkyl, optionally substituted aryl or optionallysubstituted aralkyl; and R⁷ is optionally substituted aryl or optionallysubstituted N-heteroaryl when E is —N═; or R⁷ is a monocyclicN-heteroaryl substituted with an optionally substituted aralkyl when Eis —C(R³)═ and one R² is halo, haloalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl or optionally substituted heteroarylalkyl; or R⁷is a monocyclic N-heteroaryl substituted with an optionally substitutedaralkyl when E is —C(R³)═ and one of R^(4a) and R^(4b) is not methyl andthe other is not hydrogen; or R⁷ is a monocyclic N-heteroarylsubstituted with an optionally substituted aralkyl when E is —C(R³)═ andtwo of R^(4a), R^(4b), R^(4c), and R^(4d) on adjacent carbons are notboth methyl and the other two are not both hydrogen; or R⁷ is amonocyclic N-heteroaryl substituted with an optionally substitutedaralkyl when E is —C(R³)═ and R^(4a) and R^(4b), together with thecarbon to which they are both attached, form a cycloalkyl or R^(4c) andR^(4d), together with the carbon to which they are both attached, form acycloalkyl; or R⁷ is a monocyclic N-heteroaryl substituted by an aralkylsubstituted with halo, haloalkyl, —CN, —NO₂, —N(R⁶)₂, —N(R⁶)C(O)OR⁶,—C(O)R⁶, —C(O)OR⁶ or —C(O)N(R⁶)₂ when E is —C(R³)═ and R^(4a) is methyland R^(4b), R^(4c), and R^(4d) are each hydrogen or when E is —C(R³)═and R^(4a) and R^(4c) are each methyl and R^(4b) and R^(4d) are eachhydrogen; or R⁷ is a monocyclic N-heteroaryl substituted with optionallysubstituted N-heterocyclylalkyl when E is —C(R³)═.
 20. The compound ofclaim 16 wherein: n is 1 or 2; B is —S(O)_(t) (where t is 0, 1 or 2)-; Eis —N═ or —C(R³)═; each R² is independently hydrogen, alkyl, halo,haloalkyl, optionally substituted aryl, optionally substituted aralkyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl oroptionally substituted heteroarylalkyl; or two R², together with theadjacent carbons to which they are attached, form a fused optionallysubstituted 6-membered N-heterocyclyl; each R³ is independentlyhydrogen, alkyl, haloalkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl or optionally substituted heteroarylalkyl; each R⁶ isindependently hydrogen, alkyl, haloalkyl, optionally substituted aryl oroptionally substituted aralkyl; and R⁷ is optionally substituted aryl oroptionally substituted N-heteroaryl when E is —N═; or R⁷ is a monocyclicN-heteroaryl substituted with an optionally substituted aralkyl when Eis —C(R³)═ and one R² is halo, haloalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl or optionally substituted heteroarylalkyl; or R⁷is a monocyclic N-heteroaryl substituted with an optionally substitutedaralkyl when E is —C(R³)═ and one of R^(4a) and R^(4b) is not methyl andthe other is not hydrogen; or R⁷ is a monocyclic N-heteroarylsubstituted with an optionally substituted aralkyl when E is —C(R³)═ andtwo of R^(4a), R^(4b), R^(4c), and R^(4d) on adjacent carbons are notboth methyl and the other two are not both hydrogen; or R⁷ is amonocyclic N-heteroaryl substituted with an optionally substitutedaralkyl when E is —C(R³)═ and R^(4a) and R^(4b), together with thecarbon to which they are both attached, form a cycloalkyl or R^(4c) andR^(4d), together with the carbon to which they are both attached, form acycloalkyl; or R⁷ is a monocyclic N-heteroaryl substituted by an aralkylsubstituted with halo, haloalkyl, —CN, —NO₂, —N(R⁶)₂, —N(R⁶)C(O)OR⁶,—C(O)R⁶, —C(O)OR⁶ or —C(O)N(R⁶)₂ when E is —C(R³)═ and R^(4a) is methyland R^(4b), R^(4c), and R^(4d) are each hydrogen or when E is —C(R³)═and R^(4a) and R^(4c) are each methyl and R^(4b) and R^(4d) are eachhydrogen; or R⁷ is a monocyclic N-heteroaryl substituted with optionallysubstituted N-heterocyclylalkyl when E is —C(R³)═.
 21. The compound ofclaim 15 having the formula (Ib2):

wherein: n is 1 or 2; B is —O—, —N(R⁴)—, or —S(O)_(t) (where t is 0, 1or 2)-; E is —N═ or —C(R³)═; each R² is independently hydrogen, alkyl,halo, haloalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl oroptionally substituted heteroarylalkyl; or two R², together with theadjacent carbons to which they are attached, form a fused optionallysubstituted 6-membered N-heterocyclyl; R³ is hydrogen, alkyl, haloalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl or optionallysubstituted heteroarylalkyl; R⁴ is hydrogen, alkyl, haloalkyl,optionally substituted aryl or optionally substituted aralkyl; or R⁴,together with the nitrogen to which it is attached, and a R², togetherwith the adjacent carbon to which it is attached, together form a fused6-membered N-heterocyclyl of the following structure:

where

indicates the point of fusion and R^(4a), R^(4b), R^(4c), and R^(4d) areeach independently hydrogen, alkyl, halo or haloalkyl or R^(4a) andR^(4b), together with the carbon to which they are both attached, form acycloalkyl or R^(4c) and R^(4d), together with the carbon to which theyare both attached, form a cycloalkyl, and the remaining R², if present,is selected from hydrogen, alkyl, halo or haloalkyl; each R⁶ isindependently hydrogen, alkyl, haloalkyl, optionally substituted aryl oroptionally substituted aralkyl; R⁷ is optionally substituted aryl oroptionally substituted N-heteroaryl when E is —N═; or R⁷ is a monocyclicN-heteroaryl substituted with an optionally substituted aralkyl when Eis —C(R³)═ and one R² is halo, haloalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl or optionally substituted heteroarylalkyl; or R⁷is a monocyclic N-heteroaryl substituted with an optionally substitutedaralkyl when E is —C(R³)═ and one of R^(4a) and R^(4b) is not methyl andthe other is not hydrogen; or R⁷ is a monocyclic N-heteroarylsubstituted with an optionally substituted aralkyl when E is —C(R³)═ andtwo of R^(4a), R^(4b), R^(4c), and R^(4d) on adjacent carbons are notboth methyl and the other two are not both hydrogen; or R⁷ is amonocyclic N-heteroaryl substituted with an optionally substitutedaralkyl when E is —C(R³)═ and R^(4a) and R^(4b), together with thecarbon to which they are both attached, form a cycloalkyl or R^(4c) andR^(4d), together with the carbon to which they are both attached, form acycloalkyl; or R⁷ is a monocyclic N-heteroaryl substituted by an aralkylsubstituted with halo, haloalkyl, —CN, —NO₂, —N(R⁶)₂, —N(R⁶)C(O)OR⁶,—C(O)R⁶, —C(O)OR⁶ or —C(O)N(R⁶)₂ when E is —C(R³)═ and R^(4a) is methyland R^(4b), R^(4c), and R^(4d) are each hydrogen or when E is —C(R³)═and R^(4a) and R^(4c) are each methyl and R^(4b) and R^(4d) are eachhydrogen; or R⁷ is a monocyclic N-heteroaryl substituted with optionallysubstituted N-heterocyclylalkyl when E is —C(R³)═.
 22. The compound ofclaim 21 wherein: n is 1 or 2; B is —N(R⁴)—; E is —N═ or —C(R³)═; eachR² is independently hydrogen, alkyl, halo, haloalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heteroaryl or optionally substitutedheteroarylalkyl; or two R², together with the adjacent carbons to whichthey are attached, form a fused optionally substituted 6-memberedN-heterocyclyl; R³ is hydrogen, alkyl, haloalkyl, optionally substitutedaryl, optionally substituted aralkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl or optionally substituted heteroarylalkyl; R⁴ ishydrogen, alkyl, haloalkyl, optionally substituted aryl or optionallysubstituted aralkyl; or R⁴, together with the nitrogen to which it isattached, and a R², together with the adjacent carbon to which it isattached, together form a fused 6-membered N-heterocyclyl of thefollowing structure:

where

indicates the point of fusion and R^(4a), R^(4b), R^(4c) and R^(4d) areeach independently hydrogen, alkyl, halo or haloalkyl or R^(4a) andR^(4b), together with the carbon to which they are both attached, form acycloalkyl or R^(4c) and R^(4d), together with the carbon to which theyare both attached, form a cycloalkyl, and the remaining R², if present,is selected from hydrogen, alkyl, halo or haloalkyl; each R⁶ isindependently hydrogen, alkyl, haloalkyl, optionally substituted aryl oroptionally substituted aralkyl; and R⁷ is optionally substituted aryl oroptionally substituted N-heteroaryl when E is —N═; or R⁷ is a monocyclicN-heteroaryl substituted with an optionally substituted aralkyl when Eis —C(R³)═ and one R² is halo, haloalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl or optionally substituted heteroarylalkyl; or R⁷is a monocyclic N-heteroaryl substituted with an optionally substitutedaralkyl when E is —C(R³)═ and one of R^(4a) and R^(4b) is not methyl andthe other is not hydrogen; or R⁷ is a monocyclic N-heteroarylsubstituted with an optionally substituted aralkyl when E is —C(R³)═ andtwo of R^(4a), R^(4b), R^(4c), and R^(4d) on adjacent carbons are notboth methyl and the other two are not both hydrogen; or R⁷ is amonocyclic N-heteroaryl substituted with an optionally substitutedaralkyl when E is —C(R³)═ and R^(4a) and R^(4b), together with thecarbon to which they are both attached, form a cycloalkyl or R^(4c) andR^(4d), together with the carbon to which they are both attached, form acycloalkyl; or R⁷ is a monocyclic N-heteroaryl substituted by an aralkylsubstituted with halo, haloalkyl, —CN, —NO₂, —N(R⁶)₂, —N(R⁶)C(O)OR⁶,—C(O)R⁶, —C(O)OR⁶ or —C(O)N(R⁶)₂ when E is —C(R³)═ and R^(4a) is methyland R^(4b), R^(4c), and R^(4d) are each hydrogen or when E is —C(R³)═and R^(4a) and R^(4c) are each methyl and R^(4b) and R^(4d) are eachhydrogen; or R⁷ is a monocyclic N-heteroaryl substituted with optionallysubstituted N-heterocyclylalkyl when E is —C(R³)═.
 23. The compound ofclaim 22 selected from:(R)—N-(1-(3-aminobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;(R)—N-(1-(2-aminobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;(R)—N-(1-(4-aminobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;(R)—N-(1-benzyl-1H-pyrazol-4-yl)-5-fluoro-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;(R)—N-(1-benzyl-1H-pyrazol-4-yl)-9-isopropyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;(S)—N-(1-benzyl-1H-pyrazol-4-yl)-9-trifluoromethyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;N-(1-benzyl-1H-pyrazol-4-yl)-6′-oxo-7′,8′-dihydro-6′H-spiro[cyclopropane-1,9′-pyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine]-2′-carboxamide;(R)—N-(1-(4-methylpiperazinyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;(R)—N-(1-benzyl-1H-pyrazol-4-yl)-5-chloro-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;(S)—N-(1-benzyl-1H-pyrazol-4-yl)-9-isopropyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;(R)—N-(1-benzyl-1H-pyrazol-4-yl)-9-trifluoromethyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;N-(1-benzyl-1H-pyrazol-4-yl)-9,9-dimethyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;(R)-5-fluoro-9-methyl-N-(1-((4-methylpiperazin-1-yl)methyl)-1H-pyrazol-4-yl)-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;(R)-5-fluoro-9-methyl-N-(1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;and(R)—N-(1-benzyl-1H-pyrazol-4-yl)-6-methyl-9-oxo-6,7,8,9-tetrahydropyrrolo[1,5-a:2,3-b′]dipyrazine-3-carboxamide.24. The compound of claim 21 wherein: n is 1 or 2; B is —O—; E is —N═ or—C(R³)═; each R² is independently hydrogen, alkyl, halo, haloalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl or optionallysubstituted heteroarylalkyl; or two R², together with the adjacentcarbons to which they are attached, form a fused optionally substituted6-membered N-heterocyclyl; R³ is hydrogen, alkyl, haloalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heteroaryl or optionally substitutedheteroarylalkyl; each R⁶ is independently hydrogen, alkyl, haloalkyl,optionally substituted aryl or optionally substituted aralkyl; and R⁷ isoptionally substituted aryl or optionally substituted N-heteroaryl whenE is —N═; or R⁷ is a monocyclic N-heteroaryl substituted with anoptionally substituted aralkyl when E is —C(R³)═ and one R² is halo,haloalkyl, optionally substituted aryl, optionally substituted aralkyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl oroptionally substituted heteroarylalkyl; or R⁷ is a monocyclicN-heteroaryl substituted with an optionally substituted aralkyl when Eis —C(R³)═ and one of R^(4a) and R^(4b) is not methyl and the other isnot hydrogen; or R⁷ is a monocyclic N-heteroaryl substituted with anoptionally substituted aralkyl when E is —C(R³)═ and two of R^(4a),R^(4b), R^(4c), and R^(4d) on adjacent carbons are not both methyl andthe other two are not both hydrogen; or R⁷ is a monocyclic N-heteroarylsubstituted with an optionally substituted aralkyl when E is —C(R³)═ andR^(4a) and R^(4b), together with the carbon to which they are bothattached, form a cycloalkyl or R^(4c) and R^(4d), together with thecarbon to which they are both attached, form a cycloalkyl; or R⁷ is amonocyclic N-heteroaryl substituted by an aralkyl substituted with halo,haloalkyl, —CN, —NO₂, —N(R⁶)₂, —N(R⁶)C(O)OR⁶, —C(O)R⁶, —C(O)OR⁶ or—C(O)N(R⁶)₂ when E is —C(R³)═ and R^(4a) is methyl and R^(4b), R^(4c),and R^(4d) are each hydrogen or when E is —C(R³)═ and R^(4a) and R^(4c)are each methyl and R^(4b) and R^(4d) are each hydrogen; or R⁷ is amonocyclic N-heteroaryl substituted with optionally substitutedN-heterocyclylalkyl when E is —C(R³)═.
 25. The compound of claim 21wherein: n is 1 or 2; B is —S(O)_(t) (where t is 0, 1 or 2)-; E is —N═or —C(R³)═; each R² is independently hydrogen, alkyl, halo, haloalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl or optionallysubstituted heteroarylalkyl; or two R², together with the adjacentcarbons to which they are attached, form a fused optionally substituted6-membered N-heterocyclyl; R³ is hydrogen, alkyl, haloalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heteroaryl or optionally substitutedheteroarylalkyl; each R⁶ is independently hydrogen, alkyl, haloalkyl,optionally substituted aryl or optionally substituted aralkyl; and R⁷ isoptionally substituted aryl or optionally substituted N-heteroaryl whenE is —N═; or R⁷ is a monocyclic N-heteroaryl substituted with anoptionally substituted aralkyl when E is —C(R³)═ and one R² is halo,haloalkyl, optionally substituted aryl, optionally substituted aralkyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl oroptionally substituted heteroarylalkyl; or R⁷ is a monocyclicN-heteroaryl substituted with an optionally substituted aralkyl when Eis —C(R³)═ and one of R^(4a) and R^(4b) is not methyl and the other isnot hydrogen; or R⁷ is a monocyclic N-heteroaryl substituted with anoptionally substituted aralkyl when E is —C(R³)═ and two of R^(4a),R^(4b), R^(4c), and R^(4d) on adjacent carbons are not both methyl andthe other two are not both hydrogen; or R⁷ is a monocyclic N-heteroarylsubstituted with an optionally substituted aralkyl when E is —C(R³)═ andR^(4a) and R^(4b), together with the carbon to which they are bothattached, form a cycloalkyl or R^(4c) and R^(4d), together with thecarbon to which they are both attached, form a cycloalkyl; or R⁷ is amonocyclic N-heteroaryl substituted by an aralkyl substituted with halo,haloalkyl, —CN, —NO₂, —N(R⁶)₂, —N(R⁶)C(O)OR⁶, —C(O)R⁶, —C(O)OR⁶ or—C(O)N(R⁶)₂ when E is —C(R³)═ and R^(4a) is methyl and R^(4b), R^(4c),and R^(4d) are each hydrogen or when E is —C(R³)═ and R^(4a) and R^(4c)are each methyl and R^(4b) and R^(4d) are each hydrogen; or R⁷ is amonocyclic N-heteroaryl substituted with optionally substitutedN-heterocyclylalkyl when E is —C(R³)═.
 26. The compound of claim 1having the formula (Ic):

wherein: n is 1 or 2; A is —N═ or —C(R³)═; B is —O—, —N(R⁴)—, or—S(O)_(t) (where t is 0, 1 or 2)-; E is —N═ or —C(R³)═; each R² isindependently hydrogen, alkyl, halo, haloalkyl, optionally substitutedaryl, optionally substituted aralkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl or optionally substituted heteroarylalkyl; or twoR², together with the adjacent carbons to which they are attached, forma fused optionally substituted 6-membered N-heterocyclyl; each R³ isindependently hydrogen, alkyl, haloalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl or optionally substituted heteroarylalkyl; R⁴ ishydrogen, alkyl, haloalkyl, optionally substituted aryl or optionallysubstituted aralkyl; or R⁴, together with the nitrogen to which it isattached, and a R², together with the adjacent carbon to which it isattached, together form a fused 6-membered N-heterocyclyl of thefollowing structure:

where

indicates the point of fusion and R^(4a), R^(4b), R^(4c), and R^(4d) areeach independently hydrogen, alkyl, halo or haloalkyl or R^(4a) andR^(4b), together with the carbon to which they are both attached, form acycloalkyl or R^(4c) and R^(4d), together with the carbon to which theyare both attached, form a cycloalkyl, and the remaining R², if present,is selected from hydrogen, alkyl, halo or haloalkyl; R⁵ is optionallysubstituted aryl or optionally substituted N-heteroaryl; and each R⁶ isindependently hydrogen, alkyl, haloalkyl, optionally substituted aryl oroptionally substituted aralkyl.
 27. The compound of claim 26, which is(R)-1-(1-benzyl-1H-pyrazol-4-yl)-3-(9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-2-yl)urea.28. The compound of claim 1 having the formula (Id):

wherein: n is 1 or 2; A is —N═ or —C(R³)═; B is —O—, —N(R⁴)—, or—S(O)_(t) (where t is 0, 1 or 2)-; E is —N═ or —C(R³)═; each R² isindependently hydrogen, alkyl, halo, haloalkyl, optionally substitutedaryl, optionally substituted aralkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl or optionally substituted heteroarylalkyl; or twoR², together with the adjacent carbons to which they are attached, forma fused optionally substituted 6-membered N-heterocyclyl; each R³ isindependently hydrogen, alkyl, haloalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl or optionally substituted heteroarylalkyl; R⁴ ishydrogen, alkyl, haloalkyl, optionally substituted aryl or optionallysubstituted aralkyl; or R⁴, together with the nitrogen to which it isattached, and a R², together with the adjacent carbon to which it isattached, together form a fused 6-membered N-heterocyclyl of thefollowing structure:

where

indicates the point of fusion and R^(4a), R^(4b), R^(4c), and R^(4d) areeach independently hydrogen, alkyl, halo or haloalkyl or R^(4a) andR^(4b), together with the carbon to which they are both attached, form acycloalkyl or R^(4c) and R^(4d), together with the carbon to which theyare both attached, form a cycloalkyl, and the remaining R², if present,is selected from hydrogen, alkyl, halo or haloalkyl; R⁵ is optionallysubstituted aryl or optionally substituted N-heteroaryl; and each R⁶ isindependently hydrogen, alkyl, haloalkyl, optionally substituted aryl oroptionally substituted aralkyl.
 29. The compound of claim 28, which is(R)-1-(1-benzyl-1H-pyrazol-4-yl)-3-(9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-2-yl)guanidine.30. The compound of claim 1, having the structure of formula (II):

wherein: R² is independently hydrogen, halo, C₁₋₆alkyl, orC₁₋₆haloalkyl; R^(4a) and R^(4b) are each independently hydrogen, halo,C₁₋₆alkyl, or C₁₋₆haloalkyl; or R^(4a) and R^(4b) together with thecarbon to which they are both attached, form a cycloalkyl; each R⁶ isindependently hydrogen or C₁₋₆alkyl; R¹¹ is halo, C₁₋₆haloalkyl,—N(R⁶)₂, —C₁₋₆alkyl-N(R⁶)₂, or —C(O)N(R⁶)₂; each R¹² is independently—OH, —CN, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,—N(R⁶)₂, —C₁₋₆alkyl-N(R⁶)₂, —C(O)R⁶, —C(O)OR⁶, —C(O)N(R⁶)₂, aryl,aralkyl, cycloalkyl, heterocyclyl, or heteroaryl; and n is 0, 1, 2, 3,or
 4. 31. A compound having the structure of formula (II):

wherein: R² is independently hydrogen, halo, C₁₋₆alkyl, orC₁₋₆haloalkyl; R^(4a) and R^(4b) are each independently hydrogen, halo,C₁₋₆alkyl, or C₁₋₆haloalkyl; or R^(4a) and R^(4b), together with thecarbon to which they are both attached, form a cycloalkyl; each R⁶ isindependently hydrogen or C₁₋₆alkyl; R¹ is halo, C₁₋₆haloalkyl, —N(R⁶)₂,—C₁₋₆alkyl-N(R⁶)₂, or —C(O)N(R⁶)₂; each R¹² is independently —OH, —CN,halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, —N(R⁶)₂,—C₁₋₆alkyl-N(R⁶)₂, —C(O)R⁶, —C(O)OR⁶, —C(O)N(R⁶)₂, aryl, aralkyl,cycloalkyl, heterocyclyl, or heteroaryl; and n is 0, 1, 2, 3, or 4; asan individual stereoisomer, enantiomer or tautomer thereof or a mixturethereof; or a pharmaceutically acceptable salt, solvate, or prodrugthereof.
 32. The compound of claim 30 or claim 31, wherein R² ishydrogen.
 33. The compound of claim 30 or claim 31, wherein R² is halo.34. The compound of claim 33, wherein R² is —F.
 35. The compound ofclaim 33, wherein R² is —Cl.
 36. The compound of claim 30 or claim 31,wherein R² is C₁₋₆alkyl.
 37. The compound of claim 36, wherein R² is—CH₃.
 38. The compound of any one of claims 30-37, wherein R^(4a) isC₁₋₆alkyl.
 39. The compound of claim 38, wherein R^(4a) is —CH₃.
 40. Thecompound of any one of claims 30-39, wherein R^(4b) is hydrogen.
 41. Thecompound of any one of claims 30-40, wherein each R¹² is independently—OH, —CN, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,—N(R⁶)₂, —C₁₋₆alkyl-N(R⁶)₂, —C(O)R⁶, —C(O)OR⁶, or —C(O)N(R⁶)₂.
 42. Thecompound of any one of claims 30-40, wherein each R¹² is independentlyhalo, C₁₋₆alkyl, —N(R⁶)₂, —C₁₋₆alkyl-N(R⁶)₂, or C₁₋₆haloalkyl.
 43. Thecompound of any one of claims 30-42, wherein n is
 1. 44. The compound ofany one of claims 30-40, wherein n is
 0. 45. The compound of any one ofclaims 30-44, wherein R¹¹ is halo.
 46. The compound of claim 45, whereinR¹¹ is —F.
 47. The compound of any one of claims 30-44, wherein R¹¹ isC₁₋₆haloalkyl.
 48. The compound of claim 47, wherein R¹¹ is —CF₃. 49.The compound of any one of claims 30-44, wherein R¹ is —N(R⁶)₂ or—C₁₋₆alkyl-N(R⁶)₂.
 50. The compound of claim 49, wherein R¹¹ is —N(R⁶)₂.51. The compound of claim 50, wherein R¹¹ is —NH₂.
 52. The compound ofclaim 49, wherein R¹¹ is —C₁₋₆alkyl-N(R⁶)₂.
 53. The compound of claim52, wherein R¹¹ is —CH₂NH₂.
 54. The compound of claim 1, having thestructure of formula (III):

wherein: R² is independently halo, C₁₋₆alkyl, or C₁₋₆haloalkyl; R^(4a)and R^(4b) are each independently hydrogen, halo, C₁₋₆alkyl, orC₁₋₆haloalkyl; or R^(4a) and R^(4b) together with the carbon to whichthey are both attached, form a cycloalkyl; each R⁶ is independentlyhydrogen or C₁₋₆alkyl; each R¹² is independently —OH, —CN, halo,C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, —N(R⁶)₂,—C₁₋₆alkyl-N(R⁶)₂, —C(O)R⁶, —C(O)OR⁶, —C(O)N(R⁶)₂, aryl, aralkyl,cycloalkyl, heterocyclyl, or heteroaryl; and n is 0, 1, 2, 3, or
 4. 55.A compound of formula (III):

wherein: R² is independently halo, C₁₋₆alkyl, or C₁₋₆haloalkyl; R^(4a)and R^(4b) are each independently hydrogen, halo, C₁₋₆alkyl, orC₁₋₆haloalkyl; or R^(4a) and R^(4b) together with the carbon to whichthey are both attached, form a cycloalkyl; each R⁶ is independentlyhydrogen or C₁₋₆alkyl; each R¹² is independently —OH, —CN, halo,C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, —N(R⁶)₂,—C₁₋₆alkyl-N(R⁶)₂, —C(O)R⁶, —C(O)OR⁶, —C(O)N(R⁶)₂, aryl, aralkyl,cycloalkyl, heterocyclyl, or heteroaryl; and n is 0, 1, 2, 3, or 4; asan individual stereoisomer, enantiomer or tautomer thereof or a mixturethereof; or a pharmaceutically acceptable salt, solvate, or prodrugthereof.
 56. The compound of claim 54 or claim 55, wherein R² is halo.57. The compound of claim 56, wherein R² is —F.
 58. The compound ofclaim 56, wherein R² is —Cl.
 59. The compound of claim 54 or claim 55,wherein R² is C₁₋₆alkyl.
 60. The compound of claim 59, wherein R² is—CH₃.
 61. The compound of any one of claims 54-60, wherein R^(4a) isC₁₋₆alkyl.
 62. The compound of claim 61, wherein R^(4a) is —CH₃.
 63. Thecompound of any one of claims 54-62, wherein R^(4b) is hydrogen.
 64. Thecompound of any one of claims 54-63, wherein each R¹² is independently—OH, —CN, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy,—N(R⁶)₂, —C₁₋₆alkyl-N(R⁶)₂, —C(O)R⁶, —C(O)OR⁶, or —C(O)N(R⁶)₂.
 65. Thecompound of any one of claims 54-63, wherein each R¹² is independentlyhalo, C₁₋₆alkyl, C₁₋₆haloalkyl, —N(R⁶)₂, —C₁₋₆alkyl-N(R⁶)₂, or—C(O)N(R⁶)₂.
 66. The compound of any one of claims 54-65, wherein R¹² ishalo.
 67. The compound of claim 66, wherein R¹² is —F.
 68. The compoundof claim 66, wherein R¹² is —Cl.
 69. The compound of any one of claims54-65, wherein R¹² is C₁₋₆haloalkyl.
 70. The compound of claim 69,wherein R¹² is —CF₃.
 71. The compound of any one of claims 54-65,wherein R¹² is —N(R⁶)₂ or —C₁₋₆alkyl-N(R⁶)₂.
 72. The compound of claim71, wherein R¹² is —N(R⁶)₂.
 73. The compound of claim 72, wherein R¹² is—NH₂.
 74. The compound of claim 71, wherein R¹² is —C₁₋₆alkyl-N(R⁶)₂.75. The compound of claim 74, wherein R¹² is —CH₂NH₂.
 76. The compoundof any one of claims 54-75, wherein n is
 1. 77. The compound of any oneof claims 54-63, wherein n is
 0. 78. A compound having the structure offormula (IV):

wherein:

is heterocyclyl; R² is independently hydrogen, halo, C₁₋₆alkyl, orC₁₋₆haloalkyl; R^(4a) and R^(4b) are each independently hydrogen, halo,C₁₋₆alkyl, or C₁₋₆haloalkyl; or R^(4a) and R^(4b)together with thecarbon to which they are both attached, form a cycloalkyl; each R⁶ isindependently hydrogen or C₁₋₆alkyl; R¹¹ is halo, C₁₋₆alkyl,C₁₋₆haloalkyl, —N(R⁶)₂, —C₁₋₆alkyl-N(R⁶)₂, or —C(O)N(R⁶)₂; each R¹² isindependently —OH, —CN, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy, —N(R⁶)₂, —C₁₋₆alkyl-N(R⁶)₂, —C(O)R⁶, —C(O)OR⁶,—C(O)N(R⁶)₂, aryl, aralkyl, cycloalkyl, heterocyclyl, or heteroaryl; andn is 0, 1, 2, 3, or 4; as an individual stereoisomer, enantiomer ortautomer thereof or a mixture thereof; or a pharmaceutically acceptablesalt, solvate, or prodrug thereof.
 79. The compound of claim 78, whereinR² is hydrogen.
 80. The compound of claim 78, wherein R² is halo. 81.The compound of claim 80, wherein R² is —F.
 82. The compound of claim80, wherein R² is —Cl.
 83. The compound of claim 78, wherein R² isC₁₋₆alkyl.
 84. The compound of claim 83, wherein R² is —CH₃.
 85. Thecompound of any one of claims 78-84, wherein R^(4a) is C₁₋₆alkyl. 86.The compound of claim 85, wherein R^(4a) is —CH₃.
 87. The compound ofany one of claims 78-86, wherein R^(4b) is hydrogen.
 88. The compound ofany one of claims 78-87, wherein each R¹² is independently —OH, —CN,halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, —N(R⁶)₂,—C₁₋₆alkyl-N(R⁶)₂, —C(O)R⁶, —C(O)OR⁶, or —C(O)N(R⁶)₂.
 89. The compoundof any one of claims 78-87, wherein each R¹² is independently halo,C₁₋₆alkyl, —N(R⁶)₂, —C₁₋₆alkyl-N(R⁶)₂, or C₁₋₆haloalkyl.
 90. Thecompound of any one of claims 78-89, wherein n is
 1. 91. The compound ofany one of claims 78-87, wherein n is
 0. 92. The compound of any one ofclaims 78-91, wherein R¹¹ is halo.
 93. The compound of claim 92, whereinR¹ is —F.
 94. The compound of any one of claims 78-91, wherein R¹ isC₁₋₆alkyl.
 95. The compound of claim 94, wherein R¹¹ is —CH₃.
 96. Thecompound of any one of claims 78-91, wherein R¹¹ is —N(R⁶)₂ or—C₁₋₆alkyl-N(R⁶)₂.
 97. The compound of claim 96, wherein R¹¹ is —N(R⁶)₂.98. The compound of claim 97, wherein R¹¹ is —NH₂.
 99. The compound ofclaim 96, wherein R¹¹ is —C₁₋₆alkyl-N(R⁶)₂.
 100. The compound of claim99, wherein R¹¹ is —CH₂NH₂.
 101. The compound of any one of claims78-100, wherein

is piperidine.
 102. The compound of any one of claims 76-100, wherein

is piperazine.
 103. A compound selected from:(R)-1-benzyl-N-(9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-2-yl)-1H-pyrazole-4-carboxamide;(R)—N-(1-(3-aminobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;(R)—N-(1-(2-aminobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;and(R)-1-(3-aminobenzyl)-N-(9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-2-yl)-1H-pyrazole-4-carboxamide;or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 104.A compound having the structure:(R)-9-methyl-N-(1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazol-4-yl)-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 105.A compound selected from:(R)-9-methyl-6-oxo-N-(1-(4-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;(R)—N-(1-(2,4-difluorobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;and(R)—N-(1-benzyl-1H-pyrazol-4-yl)-5-chloro-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 106.A compound having the structure:(R)—N-(1-(4-(aminomethyl)benzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 107.A compound having the structure:(R)—N-(1-(4-(aminomethyl)benzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamidehydrochloride salt; or a pharmaceutically acceptable solvate or prodrugthereof.
 108. A compound having the structure:(R)—N-(1-(4-aminobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 109.A compound having the structure:(R)—N-(1-(4-aminobenzyl)-1H-pyrazol-4-yl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamidehydrochloride salt; or a pharmaceutically acceptable solvate or prodrugthereof.
 110. A compound having the structure:(R)—N-(2-carbamoylphenyl)-9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxamide;or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 111.A pharmaceutical composition comprising a pharmaceutically acceptableexcipient and a compound of any one of claims 1-110, as an individualstereoisomer, enantiomer or tautomer thereof or a mixture thereof; or apharmaceutically acceptable salt, solvate, or prodrug thereof.
 112. Amethod of treating a disease or condition associated with p90 ribosomalS6 kinase (RSK) activity in a mammal, wherein the method comprisesadministering to the mammal a therapeutically effective amount of acompound of any one of claims 1-110, as an individual stereoisomer,enantiomer or tautomer thereof or a mixture thereof; or apharmaceutically acceptable salt, solvate, or prodrug thereof.
 113. Themethod of claim 112, wherein the disease or condition associated withRSK activity in a mammal is cancer.
 114. The method of claim 113,wherein the cancer is breast cancer, prostate cancer, lung cancer, braincancer, skin cancer, bone cancer, ovarian cancer, multiple myeloma orleukemia.
 115. The method of any one of claims 112-114, furthercomprising the administration of a second therapeutic agent.
 116. Themethod of claim 115, wherein the second therapeutic agent is achemotherapeutic agent, hormonal therapeutic agent, or animmunotherapeutic agent.
 117. The method of any one of claims 112-116,further comprising the administration of radiation therapy.